Amide compounds for treatment of medical disorders

ABSTRACT

Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein R 12  or R 13  on the A group is an amide substituent (R 32 ) are provided. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein are capable of reducing the excessive activation of complement.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional U.S. Application No.62/209,931, filed Aug. 26, 2015 and the entirety of the application ishereby incorporated by reference for all purposes.

BACKGROUND

An immune disorder occurs when the immune system is not performing in anormal manner. Inflammation is a protective response that involves theimmune system, blood vessels, and molecular mediators. A wide variety ofmedical disorders are caused by detrimental immune or inflammatoryresponses, or the inability of a cell to respond to a normal immune orinflammatory process.

The complement system is a part of the innate immune system which doesnot adapt to changes over the course of the host's life, but instead isrecruited and used by the adaptive immune system. For example, itassists, or complements, the ability of antibodies and phagocytic cellsto clear pathogens. This sophisticated regulatory pathway allows rapidreaction to pathogenic organisms while protecting host cells fromdestruction. Over thirty proteins and protein fragments make up thecomplement system. These proteins act through opsonization (enhancingphagocytosis of antigens), chemotaxis (attracting macrophages andneutrophils), cell lysis (rupturing membranes of foreign cells) andagglutination (clustering and binding of pathogens together).

The complement system has three pathways: classical, alternative andlectin. Complement Factor D plays an early and central role inactivation of the alternative pathway of the complement cascade.Activation of the alternative complement pathway is initiated byspontaneous hydrolysis of a thioester bond within C3 to produce C3(H₂O),which associates with Factor B to form the C3(H₂O)B complex. ComplementFactor D acts to cleave Factor B within the C3(H₂O)B complex to form Baand Bb. The Bb fragment remains associated with C3(H₂O) to form thealternative pathway C3 convertase C3(H₂O)Bb. Additionally, C3b generatedby any of the C3 convertases also associates with Factor B to form C3bB,which Factor D cleaves to generate the later stage alternative pathwayC3 convertase C3bBb. This latter form of the alternative pathway C3convertase may provide important downstream amplification within allthree of the defined complement pathways, leading ultimately to therecruitment and assembly of additional factors in the complement cascadepathway, including the cleavage of C5 to C5a and C5b. C5b acts in theassembly of factors C6, C7, C8, and C9 into the membrane attack complex,which can destroy pathogenic cells by lysing the cell.

The dysfunction of or excessive activation of complement has been linkedto certain autoimmune, inflammatory, and neurodegenerative diseases, aswell as ischemia-reperfusion injury and cancer. For example, activationof the alternative pathway of the complement cascade contributes to theproduction of C3a and C5a, both potent anaphylatoxins, which also haveroles in a number of inflammatory disorders. Therefore, in someinstances, it is desirable to decrease the response of the complementpathway, including the alternative complement pathway. Some examples ofdisorders mediated by the complement pathway include age-related maculardegeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiplesclerosis, and rheumatoid arthritis.

Age-related macular degeneration (AMD) is a leading cause of vision lossin industrialized countries. Based on a number of genetic studies, thereis evidence of the link between the complement cascade and maculardegeneration. Individuals with mutations in the gene encoding complementFactor H have a fivefold increased risk of macular degeneration andindividuals with mutations in other complement factor genes also have anincreased risk of AMD. Individuals with mutant Factor H also haveincreased levels of C-reactive protein, a marker of inflammation.Without adequate functioning of Factor H, the alternative pathway of thecomplement cascade is overly activated leading to cellular damage.Inhibition of the alternative pathway under these circumstances is thusdesired.

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant,hematological disorder characterized by the expansion of hematopoieticstem cells and progeny mature blood cells which are deficient in somesurface proteins. PNH erythrocytes are not capable of modulating theirsurface complement activation, which leads to the typical hallmark ofPNH—the chronic activation of complement mediated intravascular anemia.Alexion Pharmaceutical's anti-C5 antibody eculizumab (Soliris®) iscurrently the only complement-specific antibody on the market, and isthe first and only approved treatment for paroxysmal nocturnalhemoglobinuria (PNH). Exciluzimab is also approved for atypicalhemolytic uremic syndrome (aHUS). However, many of the patients treatedwith eculizumab remain anemic, and many patients continue to requireblood transfusions. In addition, treatment with eculizumab requireslife-long intravenous injections. Thus, there is an unmet need todevelop novel inhibitors of the complement pathway.

Other disorders that have been linked to the complement cascade includeaHUS, hemolytic uremic syndrome (HUS), abdominal aortic aneurysm,hemodialysis complications, hemolytic anemia, or hemodialysis,neuromylitis (NMO), myasthenia gravis (MG), fatty liver, nonalcoholicsteatohepatitis (NASH), liver inflammation, cirrhosis, liver failure,dermatomyocitis, and amyotrophic lateral sclerosis.

Factor D is an attractive target for inhibition or regulation of thecomplement cascade due to its early and essential role in thealternative complement pathway, and its potential role in signalamplification within the classical and lectin complement pathways.Inhibition of Factor D effectively interrupts the pathway and attenuatesthe formation of the membrane attack complex.

While initial attempts have been made to develop inhibitors of Factor D,there are currently no small molecule Factor D inhibitors in clinicaltrials. Examples of Factor D inhibitors or prolyl compounds aredescribed in the following disclosures.

Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled “Compoundsuseful in the complement, coagulat and kallikrein pathways and methodfor their preparation” describes fused bicyclic ring compounds that arepotent inhibitors of Factor D. Development of the Factor D inhibitorBCX1470 was discontinued due to lack of specificity and short half-lifeof the compound.

Novartis PCT patent publication WO2012/093101 titled “Indole compoundsor analogues thereof useful for the treatment of age-related maculardegeneration” describes certain Factor D inhibitors. Additional Factor Dinhibitors are described in Novartis PCT patent publicationsWO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054,WO2014/002057, WO2014/002058, WO2014/002059, WO2014/005150, andWO2014/009833.

Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Openchain prolyl urea-related modulators of androgen receptor function”describes open chain prolyl urea and thiourea related compounds for thetreatment of androgen receptor-associated conditions, such asage-related diseases, for example, sarcopenia.

Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amidederivatives and nociceptin antagonists” describes compounds with aproline-like core and aromatic substituents connected to the prolinecore through amide linkages useful for the treatment of pain.

Ferring B. V. and Yamanouchi Pharmaceutical Co. 1TD. PCT patentpublication WO1993/020099 titled “CCK and/or gastrin receptor ligands”describes compounds with a proline-like core and heterocyclicsubstituents connected to the proline core through amide linkages forthe treatment of, for example, gastric disorders or pain.

Alexion Pharmaceuticals PCT patent publication WO1995/029697 titled“Methods and compositions for the treatment of glomerulonephritis andother inflammatory diseases” discloses antibodies directed to C5 of thecomplement pathway for the treatment of glomerulonephritis andinflammatory conditions involving pathologic activation of thecomplement system.

On Feb. 25, 2015, Achillion Pharmaceuticals filed PCT Patent ApplicationNo. PCT/US2015/017523 and U.S. patent application Ser. No. 14/631,090titled “Alkyne Compounds for Treatment of Complement MediatedDisorders”; PCT Patent Application No. PCT/US2015/017538 and U.S. patentapplication Ser. No. 14/631,233 titled “Amide Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017554 and U.S. patent application Ser. No. 14/631,312 titled“Amino Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017583 and U.S. patent applicationSer. No. 14/631,440 titled “Carbamate, Ester, and Ketone Compounds forTreatment of Complement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017593 and U.S. patent application Ser. No. 14/631,625 titled“Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017597 and U.S. patent application Ser. No. 14/631,683 titled“Ether Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017600 and U.S. patent applicationSer. No. 14/631,785 titled “Phosphonate Compounds for Treatment ofComplement Mediated Disorders”; and PCT Patent Application No.PCT/US2015/017609 and U.S. patent application Ser. No. 14/631,828 titled“Compounds for Treatment of Complement Mediated Disorders.”

Given the wide variety of medical disorders that are caused bydetrimental immune or inflammatory responses, new uses and compounds areneeded for medical treatment. In one aspect, new uses and compounds areneeded to mediate the complement pathway, and for example, which act asFactor D inhibitors for treatment of disorders in a host, including ahuman, associated with dysregulation of the complement cascade, or withundesired result of the complement cascade performing its normalfunction.

SUMMARY

In a first embodiment, the invention is the use of a compound of FormulaI, or a pharmaceutically acceptable salt or composition thereof, whereinat least one of R¹² or R¹³ on the A group is an Amide substituentincluding those compounds set out in Table 1, for the treatment of adisorder in a host, typically a human, wherein the disorder is selectedfrom the group disclosed in the Detailed Description, Part IV, SectionA. The compounds of Table 1 were first disclosed in PCT PatentApplication No. PCT/US2015/017538 and U.S. patent application Ser. No.14/631,233 titled “Amide Compounds for Treatment of Complement MediatedDisorders”, however, not for the indications now provided in theDetailed Description, Part IV, Section A. The compound is provided in aneffective amount to treat the disorder, and is optionally provided in apharmaceutically acceptable carrier. Therefore, in particular, thisfirst embodiment includes uses of compounds to treat a disorder selectedfrom the group disclosed in the Detailed Description, Part IV, SectionA.

Non-limiting examples of disorders described in the DetailedDescription, Part IV, Section A include: fatty liver and conditionsstemming from fatty liver, nonalcoholic steatohepatitis (NASH), liverinflammation, cirrhosis, liver failure, dermatomyocitis, and amyotrophiclateral sclerosis. In another embodiment of Section A disorders, theactive compound is used to modulate an immune response prior to, during,or after surgery or other medical procedure, or as adjunctive therapy todampen the immune or inflammatory response during a pharmaceutical orbiopharmaceutical drug treatment, a blood transfusion, or otherallogenic tissue or fluid administration. In one embodiment, a Section Amethod is provided for the treatment or prevention of cytokine orinflammatory reactions in response to the administration ofbiotherapeutics (e.g. CAR T-cell therapy) in a host by administering aneffective amount of a designated compound herein, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier.

Non-limiting examples of disorders in the Detailed Description, Part IV,Section B of this invention include paroxysmal nocturnal hemoglobinuria(PNH), rheumatoid arthritis, multiple sclerosis, age-related maculardegeneration (AMD), retinal degeneration, other ophthalmic diseases(e.g., geographic atrophy), a respiratory disease or a cardiovasculardisease. In one aspect, an active compound or its salt or compositioncan be used to treat a medical disorder which is mediated by either adysfunctional complement cascade or a disorder or abnormality of a cellthat adversely affects the ability of the cell to engage in or respondto normal complement activity, for example, including but not limited tosparing certain cells from complement mediated lysis. PNH is one exampleof such a disorder, wherein host blood cells are missing the gene PIG-Athat expresses a protein that protects the blood cells from complementmediated lysis. Other embodiments of Section B disorders includecomplement associated disorders that are induced by antibody-antigeninteractions, a component of an immune or autoimmune disorder,hereditary angioedema, capillary leak syndrome, atypical hemolyticuremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominalaortic aneurysm, hemodialysis complications, hemolytic anemia andhemodialysis.

In a second embodiment of the invention, an amide compound is selectedfrom Table 2 or an active compound that is prepared from or consists ofmoieties selected from FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F,3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 5, 6A, and 6B; and optionally 4B, 4C,4D, 4E, 4F or a pharmaceutically acceptable composition, salt, isotopicanalog or prodrug thereof, for the treatment of an immune orinflammatory disorder in a host, typically a human, including a disorderselected from the group disclosed in the Detailed Description, Part IV,Section A or B. In one embodiment, the compound of Table 2 is used totreat a disorder associated with a dysfunction, including increasedactivity of the complement pathway that includes the administration ofan effective amount of a compound selected from Table 2 or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier, as described in more detail below.In one embodiment, the disorder is associated with the alternativecomplement cascade pathway. In yet another embodiment, the disorder isassociated with the complement classical pathway. In a furtherembodiment, the disorder is associated with the complement lectinpathway. The compound in Table in one embodiment is used to dampen orinhibit detrimental complement activity in a host, by administration ofan effective amount in a suitable manner to a host in need thereof.Therefore, in particular, this second embodiment includes compoundspecies, and uses of these species to treat disorders selected from thegroup disclosed in the Detailed Description, Part IV, Section A or B.

In a third embodiment of the invention, an amide compound is providedselected from Table 3 or a pharmaceutically acceptable composition,salt, isotopic analog or prodrug thereof, for the treatment of an immuneor inflammatory disorder in a host, typically a human, including adisorder selected from the group disclosed in the Detailed Description,Part IV, Section A or B. In one embodiment, the compound of Table 3 isused to treat a disorder associated with a dysfunction, includingincreased activity, of the complement pathway that includes theadministration of an effective amount of a compound selected from Table3 or a pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier, as described in more detail below.In one embodiment, the disorder is associated with the alternativecomplement cascade pathway. In yet another embodiment, the disorder isassociated with the complement classical pathway. In a furtherembodiment, the disorder is associated with the complement lectinpathway. The compound in Table 3 in one embodiment is used to dampen orinhibit detrimental complement activity in a host, by administration ofan effective amount in a suitable manner to a host in need thereof.Therefore, in particular, this third embodiment includes compoundspecies and uses of these species to treat a disorder selected from thegroup disclosed in the Detailed Description, Part IV, Section A or B.

In a fourth embodiment of the invention, an amide compound is providedthat is prepared from or consists of moieties selected from FIGS. 1D,1E, 5, 6A, 6B, 7A, 7B, 7C, 7D, 7E, and 8; and optionally 4B, 4C, 4D, 4Eor 4F or a pharmaceutically acceptable composition, salt, isotopicanalog or prodrug thereof, for the treatment of an immune orinflammatory disorder in a host, typically a human, including a disorderselected from the group disclosed in the Detailed Description, Part IV,Section A. In one embodiment, the compound that is prepared from orconsists of moieties selected from FIGS. 1D, 1E, 5, 6A, 6B, 7A, 7B, 7C,7D, 7E, and 8; and optionally 4B, 4C, 4D, 4E, or 4F is used to treat adisorder associated with a dysfunction, including increased activity, ofthe complement pathway that includes the administration of an effectiveamount of the compound or an embodiment of the active compound, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier, as described in more detail below.In one embodiment, the disorder is associated with the alternativecomplement cascade pathway. In yet another embodiment, the disorder isassociated with the complement classical pathway. In a furtherembodiment, the disorder is associated with the complement lectinpathway. The compound in one embodiment provided herein is used todampen or inhibit detrimental complement activity in a host, byadministration of an effective amount in a suitable manner to a host inneed thereof. Therefore, in particular, this fourth embodiment includesuses of these compounds to treat disorder selected from the groupdisclosed in the Detailed Description, Part IV, Section A.

In a fifth embodiment of the invention, an amide compound is providedthat is prepared from or consists of moieties selected from FIGS. 1B,1C, 1D, 1E, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O,3P, 3Q, 5, 6A, 6B, 6C, and 7F; and optionally 4B, 4C, 4D, 4E, and 4F ora pharmaceutically acceptable composition, salt, isotopic analog orprodrug thereof, for the treatment of an immune or inflammatory disorderin a host, typically a human, including a disorder selected from thegroup disclosed in the Detailed Description, Part IV, Section A or B. Inone embodiment, the compound that is prepared from or consists ofmoieties selected from FIGS. 1B, 1C, 1D, 1E, 3A, 3B, 3C, 3D, 3E, 3F, 3G,3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 5, 6A, 6B, 6C, and 7F; andoptionally 4B, 4C, 4D, 4E, and 4F is used to treat a disorder associatedwith a dysfunction, including increased activity, of the complementpathway that includes the administration of an effective amount of thecompound or an embodiment of the active compound, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier, as described in more detail below. In one embodiment, thedisorder is associated with the alternative complement cascade pathway.In yet another embodiment, the disorder is associated with thecomplement classical pathway. In a further embodiment, the disorder isassociated with the complement lectin pathway. The compound in oneembodiment provided herein is used to dampen or inhibit detrimentalcomplement activity in a host, by administration of an effective amountin a suitable manner to a host in need thereof. Therefore, inparticular, this fifth embodiment includes compound species and uses ofthese species to treat disorder selected from the group disclosed in theDetailed Description, Part IV, Section A or B.

In a sixth embodiment of the invention, an amide compound is providedthat is prepared from or consists of moieties selected from FIGS. 1B,1C, 1D, 1E, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O,3P, 3Q, 5, 6A, 6B, 6C, 7G and 8; and optionally 4B, 4C, 4D, 4E, 4F or apharmaceutically acceptable composition, salt, isotopic analog orprodrug thereof, for the treatment of an immune or inflammatory disorderin a host, typically a human, including a disorder selected from thegroup disclosed in the Detailed Description, Part IV, Section A. In oneembodiment, the compound that is prepared from or consists of moietiesselected from FIGS. 1B, 1C, 1D, 1E, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I,3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 5, 6A, 6B, 6C, 7G and 8; and optionally4B, 4C, 4D, 4E, 4F is used to treat a disorder associated with adysfunction, including increased activity, of the complement pathwaythat includes the administration of an effective amount of the compoundor an embodiment of the active compound, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier, as described in more detail below. In one embodiment, thedisorder is associated with the alternative complement cascade pathway.In yet another embodiment, the disorder is associated with thecomplement classical pathway. In a further embodiment, the disorder isassociated with the complement lectin pathway. The compound in oneembodiment provided herein is used to dampen or inhibit detrimentalcomplement activity in a host, by administration of an effective amountin a suitable manner to a host in need thereof. Therefore, inparticular, this sixth embodiment includes uses of these species totreat disorder selected from the group disclosed in the DetailedDescription, Part IV, Section A.

In a seventh embodiment of the invention, an amide compound as describedand used herein is selected from those depicted in FIGS. 9A, 9B, 9C, 9D,9E, 9F, 9G and 9H, and FIGS. 6A, and 6B or a pharmaceutically acceptablecomposition, salt, isotopic analog or prodrug thereof, for the treatmentof an immune or inflammatory disorder in a host, typically a human,including a disorder selected from the group disclosed in the DetailedDescription, Part IV, Section A or B. In one embodiment, the compound ofFIG. 9A, 9B, 9C, 9D, 9E, 9F, 9G or 9H, and FIG. 6A, or 6B is used totreat a disorder associated with a dysfunction, including increasedactivity of the complement pathway that includes the administration ofan effective amount of a compound selected from FIG. 9A, 9B, 9C, 9D, 9E,9F, 9G or 9H, and FIG. 6A, or 6B or a pharmaceutically acceptable saltthereof, optionally in a pharmaceutically acceptable carrier, asdescribed in more detail below. In one embodiment, the disorder isassociated with the alternative complement cascade pathway. In yetanother embodiment, the disorder is associated with the complementclassical pathway. In a further embodiment, the disorder is associatedwith the complement lectin pathway. The compound in FIG. 9A, 9B, 9C, 9D,9E, 9F, 9G or 9H, and FIG. 6A, or 6B in one embodiment is used to dampenor inhibit detrimental complement activity in a host, by administrationof an effective amount in a suitable manner to a host in need thereof.Therefore, in particular, this seventh embodiment includes compoundspecies, and uses of these species to treat disorder selected from thegroup disclosed in the Detailed Description, Part IV, Section A or B.

Compounds disclosed herein or used as described herein may beadministered in any desired route according to the direction of thehealthcare provider, for example, oral, topical, parenteral, byinhalation or spray, sublingual, via implant, including ocular implant,transdermal, via buccal administration, rectal, as an ophthalmicsolution, injection, including ocular injection, intravenous,intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous,transnasal, sublingual, or rectal or by other means, in dosage unitformulations optionally containing conventional pharmaceuticallyacceptable carriers, and in an immediate or controlled release fashion.For use in the eye, any of the compounds described herein can beadministered to the eye in any desired form of administration, includingvia intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal,retro-bulbar, peribulbar, suprachoroidal, choroidal, subchoroidal,conjunctival, subconjunctival, episcleral, posteriorjuxtascleralscleral, circumcorneal, and tear duct injections, or througha mucus, mucin, or a mucosal barrier, in an immediate or controlledrelease fashion.

The compounds of Formula I as described in PCT Patent Application No.PCT/US2015/017538 and U.S. patent application Ser. No. 14/631,233 titled“Amide Compounds for Treatment of Complement Mediated Disorders” are ofthe formula:

and the pharmaceutically acceptable salts and compositions thereof,wherein:

Q¹ is N(R¹) or C(R¹R^(1′));

Q² is C(R²R^(2′)), C(R²R^(2′))—C(R²R²⁺′), S, O, N(R²) or C(R²R^(2′))O;

Q³ is N(R³), S, or C(R³R^(3′));

X¹ and X² are independently N, CH, or CZ, or X¹ and X² together are C═C;and

wherein Q¹, Q², Q³, X¹, and X² are selected such that a stable compoundresults.

Any of the structures illustrated herein, e.g., A, B, L or central corecan be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, andindependently, selected from R⁷⁵, wherein R⁷⁵ is selected from hydrogen,halogen, hydroxyl, nitro, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆thioalkyl, C₁-C₆alkoxy,-JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)NR²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,-JC(O)OR²³; each of which R⁷⁵ may be unsubstituted or substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂, —P(O)(OH)₂,C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, —C₀-C₄alkyl(mono-and)di-C₁-C₄alkylNR⁹R¹⁰, C₁-C₆alkylester, C₁-C₄alkylamino,C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —OC(O)R⁹,—NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy, S(O)═NHR²¹, SF₅, and JC(R⁹)═NR²¹ and SO₂OR²¹.

In an alternate embodiment, the

ring is replaced by one of the following core structures:

wherein q is 0, 1, 2 or 3, r is 1, 2 or 3,

is a single or double bond. Examples of core structures are provided inFIGS. 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q,and 5.

It is clear that when q is 0,

is not a double bond.

R and R′ (see FIG. 5) are independently selected from H, alkyl,cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl wherein each group can beoptionally substituted or any other substituent group herein thatprovides the desired properties. In some embodiments, the core ringincludes one or more chiral carbon atoms. The invention includes the useof compounds with embodiments in which the chiral carbon can be providedas an enantiomer, or mixtures of enantiomers, including a racemicmixture. Where the core ring includes more than one stereocenter, all ofthe enantiomers and diastereomers are included in the invention asindividual species.

Z is F, Cl, NH₂, CH₃, CH₂D, CHD₂, or CD₃.

R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently selected ateach occurrence, as appropriate, and only where a stable compoundresults, from hydrogen, halogen, hydroxyl, nitro, cyano, amino,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkynyl,C₂-C₆alkanoyl, C₁-C₆thioalkyl, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl,—C₀-C₄alkylNR⁹R¹⁰, —C(O)OR⁹, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰,—OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, whereR⁹ and R¹⁰ are independently selected at each occurrence from hydrogen,C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl).

In alternative embodiments, R¹ and R^(1′) or R³ and R^(3′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring or a 3- to6-membered heterocyclic spiro ring containing 1 or 2 heteroatomsindependently selected from N, O, or S; R² and R^(2′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring; or R² andR^(2′) may be taken together to form a 3- to 6-membered heterocyclicspiro ring; each of which spiro ring may be unsubstituted or substitutedwith 1 or more substituents independently selected from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In alternative embodiments, R¹ and R² may be taken together to form a3-membered carbocyclic ring; R¹ and R² may be taken together to form a4- to 6-membered carbocyclic or aryl ring or a 4- to 6-memberedheterocyclic or heteroaryl ring containing 1 or 2 heteroatomsindependently selected from N, O, and S; or R² and R³, if bound toadjacent carbon atoms, may be taken together to form a 3- to 6-memberedcarbocyclic or aryl ring or a 3- to 6-membered heterocyclic orheteroaryl ring; each of which ring may be unsubstituted or substitutedwith 1 or more substituents independently selected from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In alternative embodiments, R¹ and R^(1′), R² and R^(2′), or R³ andR^(3′) can be taken together to form a carbonyl group. In alternativeembodiments, R¹ and R² or R² and R³ can be taken together to form acarbon-carbon double bond.

Non-limiting examples of the

ring are illustrated, for example, in FIG. 5 (any of which can beotherwise substituted with R¹, R^(1′), R², R^(2′), R³, and R^(3′)).

A is a group selected from:

Examples of “A” groups are in FIGS. 1B, 1C, 1D, and 1E.

R⁴ is selected from —CHO, —CONH₂, C₂-C₆alkanoyl, hydrogen, —SO₂NH₂,—C(CH₂)₂F, —CH(CF₃)NH₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₂alkyl(C₃-C₇cycloalkyl),

each of which R⁴ other than hydrogen, —CHO, and —CONH₂, is unsubstitutedor substituted with one or more of amino, imino, halogen, hydroxyl,cyano, cyanoimino, C₁-C₂alkyl, C₁-C₂alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R⁵ and R⁶ are independently selected from —CHO, —C(O)NH₂, —C(O)NH(CH₃),C₂-C₆alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH,—SO₂NH₂, vinyl, C₁-C₆alkyl (including methyl), C₂-C₆alkenyl,C₁-C₆alkoxy, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl), —P(O)(OR⁹)₂, —OC(O)R⁹, —C(O)OR⁹,—C(O)N(CH₂CH₂R⁹)(R¹⁰), —NR⁹C(O)R¹⁰, phenyl, or 5- to 6-memberedheteroaryl.

Each R⁵ and R⁶ other than hydrogen, hydroxyl, cyano, and —COOH isunsubstituted or optionally substituted. For example, R⁵ and R⁶ otherthan hydrogen, hydroxyl, cyano, and —COOH may be substituted with one ormore substituents independently selected from halogen, hydroxyl, amino,imino, cyano, cyanoimino, C₁-C₂alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R^(6′) is hydrogen, halogen, hydroxyl, C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), or C₁-C₄alkoxy; or R⁶ and R^(6′) may betaken together to form an oxo, vinyl, or imino group.

R⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl).

R⁸ and R^(8′) are independently selected from hydrogen, halogen,hydroxyl, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) can be taken together with the carbonthat they are bonded to form a 3-membered carbocyclic ring.

R¹⁶ is absent or be independently selected from halogen, hydroxyl,nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R¹⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,—SO₂C₁-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(C₃-C₇heterocycloalkyl),—C₀-C₄alkyl(aryl), C₀-C₄alkyl(heteroaryl), and wherein R¹⁹ other thanhydrogen is unsubstituted or substituted with one or more substituentsindependently selected from halogen, hydroxyl, amino, —COOH, and—C(O)OC₁-C₄alkyl.

X¹¹ is N or CR¹¹.

X¹² is N or CR¹².

X¹³ is N or CR¹³.

X¹⁴ is N or CR¹⁴.

No more than 2 of X¹¹, X¹, X¹³, and X¹⁴ are N.

One of R¹² or R¹³ is R³². In one embodiment, one of R¹² and R¹³ isselected from R³¹ and the other of R¹² and R¹³ is selected from R³². Inan alternative embodiment, R¹² and R¹³ are each independently selectedfrom an R³² moiety.

R³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and —C(NR⁹)NR⁹R¹⁰, each ofwhich R³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy is unsubstituted or substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, amino, —COOH, —CONH₂C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,and each of which R³¹ is also optionally substituted with onesubstituent selected from phenyl and 4- to 7-membered heterocyclecontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS; which phenyl or 4- to 7-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl)(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, andC₁-C₂haloalkoxy;

R³² is selected from C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, and —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted.

R³² is the same as Z₃₂.

In one embodiment, when R³² is C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, Bis not C₂-C₆ alkenyl; (C₀-C₄ alkyl)(heteroaryl); monocyclic or bicycliccarbocyclic; or monocyclic heterocyclic.

R²¹ and R²² are independently selected at each occurrence from hydrogen,hydroxyl, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and each R²¹ and R²² can be optionallysubstituted.

R²³ is independently selected at each occurrence from C₁-C₆alkyl,C₁-C₆haloalkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, (4- to7-membered heterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S, and (5- or 6-memberedunsaturated or aromatic heterocycle)C₀-C₄alkyl having 1, 2, or 3heteroatoms independently selected from N, O, and S.

R²⁴ and R²⁵ are taken together with the nitrogen to which they areattached to form a 4- to 7-membered monocyclic heterocycloalkyl group,or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro,or bridged rings and each R²⁴ and R²⁵ can be optionally substituted.

R³⁷ is selected at each occurrence from hydroxyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and each can be optionally substituted.

When A is an indole or indazole and X¹² is N, X¹³ is CR¹³, wherein R¹³is R³².

When A is an indole or indazole and X¹³ is N, X¹² is CR¹², wherein R¹²is R³².

R¹¹, R¹⁴, and R¹⁵ are independently selected at each occurrence fromhydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₂-C₆alkenyl(aryl),C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), C₂-C₆alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

L is a bond or is selected from the formulas

where R¹⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl) andR¹⁸ and R^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.

Linkers are also illustrated in FIGS. 4B, 4C, 4D, 4E, 4F, and 4G.

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicycliccarbocyclicoxy group; a monocyclic, bicyclic, or tricyclic heterocyclicgroup having 1, 2, 3, or 4 heteroatoms independently selected from N, O,and S and from 4 to 7 ring atoms per ring; C₂-C₆alkenyl; C₂-C₆alkynyl;—(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl), and B is unsubstituted or substituted with oneor more substituents independently selected from R³³ and R³⁴, and 0 or 1substituents selected from R³⁵ and R³⁶.

R³³ is independently selected from halogen, hydroxyl, —COOH, cyano,C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R³⁴ is independently selected from nitro, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹ _(COR) ²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)NR²², -JC(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)NR²⁴R²⁵,-JNR⁹C(O)R²², -JC(O)R₂₁, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,and -JC(O)OR²³; each of which R³⁴ may be unsubstituted or substitutedwith one or more substituents independently selected from halogen,hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂,—P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy,—C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

R³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4-to 7-membered heterocycloalkyl)C₀-C₄alkyl containing 1 or 2 heteroatomsselected from N, O, and S, and bicyclic heterocycle containing 1, 2, or3 heteroatoms independently selected from N, O, and S, and containing 4-to 7-ring atoms in each ring; each of which R³⁵ is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

R³⁶ is independently selected from tetrazolyl, (phenyl)C₀-C₂alkyl,(phenyl)C₁-C₂alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently selected from N, O, B, and S, eachof which R³⁶ is unsubstituted or substituted with one or moresubstituents independently selected from halogen, hydroxyl, nitro,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, —OSi(CH₃)₂C(CH₃)₃,—Si(CH₃)₂C(CH₃)₃, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

J is independently selected at each occurrence from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene.

In one additional alternative embodiment B is selected from:

In one additional alternative embodiment R³⁶ is selected from:

In one embodiment R¹ is selected from F, Cl, Br, and C₁-C₆alkyl.

In one embodiment R¹ is selected from hydroxyl and C₁-C₆alkoxy.

In one embodiment R¹ is selected from C₂-C₆alkynyl, C₂-C₆alkanoyl, andC₁-C₆thioalkyl.

In one embodiment R¹ is selected from aminoC₁-C₆alkyl and—C₀-C₄alkylNR⁹R¹⁰.

The present invention thus includes at least the following features:

-   (a) An amide compound of Formula I, including those compounds listed    in Table 1, as described herein, and pharmaceutically acceptable    salts and prodrugs thereof, for use in treating or preventing a    disorder listed in the Detailed Description, Part IV, Section A,    including but not limited to the development of fatty liver and    conditions stemming from fatty liver, such as nonalcoholic    steatohepatitis (NASH), liver inflammation, cirrhosis, liver    failure; dermatomyocitis; amyotrophic lateral sclerosis; and    cytokine or inflammatory reactions in response to biotherapeutics    (e.g. CAR T-cell therapy);-   (b) An amide compound of Table 2 or Table 3 or an active compound    that is prepared from or consists of moieties selected from FIGS.    1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L,    3M, 3N, 6A, and 6B, optionally 4B, 4C, 4D, 4E or 4F, as described    herein, and pharmaceutically acceptable salts and prodrugs thereof,    for use in treating or preventing a disorder listed in the Detailed    Description, Part IV, Section A, including but not limited to the    development of fatty liver and conditions stemming from fatty liver,    such as nonalcoholic steatohepatitis (NASH), liver inflammation,    cirrhosis, liver failure, dermatomyocitis; amyotrophic lateral    sclerosis; and cytokine or inflammatory reactions in response to the    administration of biotherapeutics (e.g. CAR T-cell therapy);-   (c) An amide compound of Table 2 or Table 3 or an embodiment of the    active compound as described in FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B,    3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 6A, and 6B,    optionally 4B, 4C, 4D, 4E or 4F, as described herein, and    pharmaceutically acceptable salts and prodrugs thereof, for use in    treating or preventing a disorder listed in the Detailed    Description, Part IV, Section B of this invention, including but not    limited to paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid    arthritis, multiple sclerosis, age-related macular degeneration    (AMD), retinal degeneration, other ophthalmic diseases (e.g.,    geographic atrophy), a respiratory disease or a cardiovascular    disease;-   (d) A pharmaceutically acceptable composition of an amide compound    of Table 2 or Table 3 or a amide compound that is prepared from or    consists of moieties selected from FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B,    3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 6A, and 6B,    optionally 4B, 4C, 4D, 4E or 4F, or its pharmaceutically acceptable    salt in a pharmaceutically acceptable carrier;-   (e) An amide compound selected from Table 2 or Table 3 or a compound    that is prepared from or consists of moieties selected from FIGS.    1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L,    3M, 3N, 6A, and 6B, optionally 4B, 4C, 4D, 4E or 4F, as described    herein, and pharmaceutically acceptable salts, prodrugs and    pharmaceutically acceptable compositions thereof;-   (f) An amide compound selected from Table 2 or Table 3 or a compound    that is prepared from or consists of moieties selected from FIGS.    1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L,    3M, 3N, 6A, and 6B, optionally 4B, 4C, 4D, 4E or 4F, as described    herein, and pharmaceutically acceptable salts and prodrugs thereof,    for use in treating or preventing disorders mediated by the    complement pathway, and for example, cascade Factor D;-   (g) Use of a compound of Formula I, including those compounds listed    in Table 1, as described herein, and pharmaceutically acceptable    salts and prodrugs thereof, in the manufacture of a medicament for    treating or preventing a disorder listed in the Detailed    Description, Part IV, Section A, including but not limited to the    development of fatty liver and conditions stemming from fatty liver,    such as nonalcoholic steatohepatitis (NASH), liver inflammation,    cirrhosis, liver failure; dermatomyocitis; amyotrophic lateral    sclerosis; and cytokine or inflammatory reactions in response to    biotherapeutics (e.g. CAR T-cell therapy);-   (h) Use of a compound of Table 2 or Table 3 that is prepared from or    consists of moieties selected from FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B,    3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 6A, and 6B,    optionally 4B, 4C, 4D, 4E or 4F, as described herein, and    pharmaceutically acceptable salts and prodrugs thereof, in the    manufacture of a medicament for treating or preventing a disorder    listed in the Detailed Description, Part IV, Section A, including    but not limited to the development of fatty liver and conditions    stemming from fatty liver, such as nonalcoholic steatohepatitis    (NASH), liver inflammation, cirrhosis, liver failure;    dermatomyocitis; amyotrophic lateral sclerosis; and cytokine or    inflammatory reactions in response to biotherapeutics (e.g. CAR    T-cell therapy);-   (i) Use of a compound of Table 2 or Table 3 or a compound that is    prepared from or consists of moieties selected from FIGS. 1B, 1C,    2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N,    6A, and 6B, optionally 4B, 4C, 4D, 4E or 4F, as described herein,    and pharmaceutically acceptable salts and prodrugs thereof, in the    manufacture of a medicament for treating or preventing a disorder    listed in the Detailed Description, Part IV, Section B of this    invention, including but not limited to paroxysmal nocturnal    hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis,    age-related macular degeneration (AMD), retinal degeneration, other    ophthalmic diseases (e.g., geographic atrophy), a respiratory    disease or a cardiovascular disease;-   (j) A process for manufacturing a medicament intended for the    therapeutic use for treating or preventing a disorder listed in the    Detailed Description, Part IV, Section A or Section B, or generally    for treating or preventing disorders mediated by complement cascade    Factor D, including age-related macular degeneration (AMD), retinal    degeneration, paroxysymal nocturnal hemoglobinuria (PNH), multiple    sclerosis (MS), and rheumatoid arthritis (RA) and other disorders    described further herein characterized in that a compound selected    from Table 2 or Table 3 or a compound that is prepared from or    consists of moieties selected from FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B,    3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 6A, and 6B,    optionally 4B, 4C, 4D, 4E or 4F, is used in the manufacture;-   (k) A compound selected from Table 2 or Table 3 or a compound that    is prepared from or consists of moieties selected from FIGS. 1B, 1C,    2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N,    6A, and 6B, optionally 4B, 4C, 4D, 4E or 4F, as described herein in    substantially pure form (e.g., at least 90 or 95%):-   (l) An amide compound of Formula I, including those compounds listed    in Table 1, as described herein, and pharmaceutically acceptable    salts and prodrugs thereof, for use in treating a medical disorder    which is an inflammatory or immune condition, a disorder mediated by    the complement cascade (including a dysfunctional cascade), a    disorder or abnormality of a cell that adversely affects the ability    of the cell to engage in or respond to normal complement activity,    or an undesired complement-mediated response to a medical treatment,    such as surgery or other medical procedure or a pharmaceutical or    biopharmaceutical drug administration, a blood transfusion, or other    allogenic tissue or fluid administration;-   (m) An amide compound of Table 2 or Table 3 or a compound that is    prepared from or consists of moieties in FIGS. 1B, 1C, 2B, 2C, 2D,    2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 6A, and 6B,    optionally 4B, 4C, 4D, 4E or 4F, as described herein, and    pharmaceutically acceptable salts and prodrugs thereof, for use in    treating a medical disorder which is an inflammatory or immune    condition, a disorder mediated by the complement cascade (including    a dysfunctional cascade), a disorder or abnormality of a cell that    adversely affects the ability of the cell to engage in or respond to    normal complement activity, or an undesired complement-mediated    response to a medical treatment, such as surgery or other medical    procedure or a pharmaceutical or biopharmaceutical drug    administration, a blood transfusion, or other allogenic tissue or    fluid administration;-   (n) An amide compound that is prepared from or consists of moieties    selected from FIG. 1D or 1E; 5; 6A, 6B, 7A, 7B, 7C, 7D or 7E; and 8;    optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F, as    described herein, and pharmaceutically acceptable salts and prodrugs    thereof, for use in treating or preventing a disorder listed in the    Detailed Description, Part IV, Section A, including but not limited    to the development of fatty liver and conditions stemming from fatty    liver, such as nonalcoholic steatohepatitis (NASH), liver    inflammation, cirrhosis, liver failure; dermatomyocitis; amyotrophic    lateral sclerosis; and cytokine or inflammatory reactions in    response to biotherapeutics (e.g. CAR T-cell therapy);-   (o) An amide compound that is prepared from or consists of moieties    selected from one of the following groups: (i) any of FIG. 1B, 1C,    1D or 1E; FIG. 5; FIG. 6A, 6B, or 6C and FIG. 7F; optionally    including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; (ii) FIGS. 1B, 1C,    2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N,    3O, 3P, 3Q, 6A, 6B, 6C, and 7F; optionally including a moiety of    FIG. 4B, 4C, 4D, 4E or 4F; (iii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B,    3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B,    6C, and 7G; optionally including a moiety of FIG. 4B, 4C, 4D, 4E or    4F; (iv) FIG. 1B, 1C, 1D or 1E; FIG. 5; FIG. 6E; any of FIGS. 7A,    7B, 7C, 7D, 7E, 7F, 7G and 8; optionally including a moiety of FIG.    4B, 4C, 4D, 4E or 4F or (v) FIGS. 9A, 9B, 9C, 9D, 9E, 9F, 9G, 9H and    FIGS. 6A, 6B and 6C; as described herein, and pharmaceutically    acceptable salts and prodrugs thereof, for use in treating or    preventing a disorder listed in the Detailed Description, Part IV,    Section A, including but not limited to the development of fatty    liver and conditions stemming from fatty liver, such as nonalcoholic    steatohepatitis (NASH), liver inflammation, cirrhosis, liver    failure, dermatomyocitis; amyotrophic lateral sclerosis; and    cytokine or inflammatory reactions in response to the administration    of biotherapeutics (e.g. CAR T-cell therapy);-   (p) An amide compound that is prepared from or consists of moieties    selected from one of the following groups: (i) any of FIG. 1B, 1C,    1D or 1E; FIG. 5; any one of FIGS. 6A, 6B, 6C and FIG. 7F,    optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; (ii    FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,    3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7F; optionally including    a moiety of FIG. 4B, 4C, 4D, 4E or 4F; (iii) FIGS. 1B, 1C, 2B, 2C,    2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P,    3Q, 6A, 6B, 6C, and 7G; optionally including a moiety of FIG. 4B,    4C, 4D, 4E or 4F; (iv) FIG. 1B, 1C, 1D or 1E; FIG. 5; FIG. 6E; any    of FIGS. 7A, 7B, 7C, 7D, 7E, 7F, 7G and 8; optionally including a    moiety of FIG. 4B, 4C, 4D, 4E or 4F or (v) FIGS. 9A, 9B, 9C, 9D, 9E,    9F, 9G, 9H and FIGS. 6A, 6B and 6C; as described herein, and    pharmaceutically acceptable salts and prodrugs thereof, for use in    treating or preventing a disorder listed in the Detailed    Description, Part IV, Section B of this invention, including but not    limited to paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid    arthritis, multiple sclerosis, age-related macular degeneration    (AMD), retinal degeneration, other ophthalmic diseases (e.g.,    geographic atrophy), a respiratory disease or a cardiovascular    disease;-   (q) A pharmaceutically acceptable composition of a compound of any    species consisting of moieties selected from one of the following    groups: (i) any of FIG. 1B, 1C, 1D or 1E; FIG. 5; any one of FIGS.    6A, 6B, 6C and FIG. 7F; optionally including a moiety of FIG. 4B,    4C, 4D, 4E or 4F; (ii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E,    3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7F;    optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; (iii)    FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,    3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7G; optionally including    a moiety of FIG. 4B, 4C, 4D, 4E or 4F; (iv) FIG. 1B, 1C, 1D or 1E;    FIG. 5; FIG. 6E; any of FIGS. 7A, 7B, 7C, 7D, 7E, 7F, 7G and 8;    optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F or (v)    FIGS. 9A, 9B, 9C, 9D, 9E, 9F, 9G, 9H and FIGS. 6A, 6B and 6C; or its    pharmaceutically acceptable salt in a pharmaceutically acceptable    carrier;-   (r) A compound that is prepared from or consists of moieties    selected from one of the following groups (i) any of FIG. 1B, 1C, 1D    or 1E; FIG. 5; any one of FIGS. 6A, 6B, 6C and FIG. 7F; optionally    including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; or (ii) FIGS. 1B,    1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M,    3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7F; optionally including a moiety of    FIG. 4B, 4C, 4D, 4E or 4F; as described herein, and pharmaceutically    acceptable salts, prodrugs and pharmaceutically acceptable    compositions thereof;-   (s) A compound that is prepared from or consists of moieties    selected from one of the following groups (i) any of FIG. 1B, 1C, 1D    or 1E; FIG. 5; any one of FIGS. 6A, 6B, and 6C and FIG. 7F;    optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; (ii)    FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,    3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7F; optionally including    a moiety of FIG. 4B, 4C, 4D, 4E or 4F; or (iii) FIGS. 1B, 1C, 2B,    2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O,    3P, 3Q, 6A, 6B, 6C, and 7G; optionally including a moiety of FIG.    4B, 4C, 4D, 4E or 4F; as described herein, and pharmaceutically    acceptable salts and prodrugs thereof, for use in treating or    preventing disorders mediated by the complement pathway, and for    example, cascade Factor D;-   (t) Use of a compound that is prepared from or consists of moieties    selected from FIG. 1D or 1E; 5; 6A, 6B, 6C; 7A, 7B, 7C, 7D or 7E;    and 8; optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F as    described herein, and pharmaceutically acceptable salts and prodrugs    thereof, in the manufacture of a medicament for treating or    preventing a disorder listed in the Detailed Description, Part IV,    Section A, including but not limited to the development of fatty    liver and conditions stemming from fatty liver, such as nonalcoholic    steatohepatitis (NASH), liver inflammation, cirrhosis, liver    failure; dermatomyocitis; amyotrophic lateral sclerosis; and    cytokine or inflammatory reactions in response to biotherapeutics    (e.g. CAR T-cell therapy);-   (u) Use of a compound of that is prepared from or consists of    moieties selected from (i) any of FIG. 1B, 1C, 1D or 1E; FIG. 5; any    one of FIGS. 6A, 6B, 6C and FIG. 7F; optionally including a moiety    of FIG. 4B, 4C, 4D, 4E or 4F; (ii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B,    3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B,    6C, and 7F; optionally including a moiety of FIG. 4B, 4C, 4D, 4E or    4F; or (iii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G,    3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7G;    optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; as    described herein, and pharmaceutically acceptable salts and prodrugs    thereof, in the manufacture of a medicament for treating or    preventing a disorder listed in the Detailed Description, Part IV,    Section A, including but not limited to the development of fatty    liver and conditions stemming from fatty liver, such as nonalcoholic    steatohepatitis (NASH), liver inflammation, cirrhosis, liver    failure; dermatomyocitis; amyotrophic lateral sclerosis; and    cytokine or inflammatory reactions in response to biotherapeutics    (e.g. CAR T-cell therapy);-   (v) Use of a compound that is prepared from or consists of moieties    selected from (i) any of FIG. 1B, 1C, 1D or 1E; FIG. 5; any one of    FIGS. 6A, 6B, 6C and FIG. 7F; optionally including a moiety of FIG.    4B, 4C, 4D, 4E or 4F; (ii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D,    3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and    7F; optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F;    or (iii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H,    3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7G; optionally    including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; as described    herein, and pharmaceutically acceptable salts and prodrugs thereof,    in the manufacture of a medicament for treating or preventing a    disorder listed in the Detailed Description, Part IV, Section B of    this invention, including but not limited to paroxysmal nocturnal    hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis,    age-related macular degeneration (AMD), retinal degeneration, other    ophthalmic diseases (e.g., geographic atrophy), a respiratory    disease or a cardiovascular disease;-   (w) A process for manufacturing a medicament intended for the    therapeutic use for treating or preventing a disorder listed in the    Detailed Description, Part IV, Section A or Section B, or generally    for treating or preventing disorders mediated by complement cascade    Factor D, including age-related macular degeneration (AMD), retinal    degeneration, paroxysymal nocturnal hemoglobinuria (PNH), multiple    sclerosis (MS), and rheumatoid arthritis (RA) and other disorders    described further herein characterized in that a compound selected    for use is a compound that is prepared from or consists of moieties    selected from (i) any of FIG. 1B, 1C, 1D or 1E; FIG. 5; any one of    FIGS. 6A, 6B, 6C and FIG. 7F; optionally including a moiety of FIG.    4B, 4C, 4D, 4E or 4F; (ii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D,    3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and    7F; optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F;    or (iii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H,    3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7G; optionally    including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; as described herein    is used in the manufacture;-   (x) A compound that is prepared from or consists of moieties    selected from (i) any of FIG. 1B, 1C, 1D or 1E; FIG. 5; any one of    FIGS. 6A, 6B, 6C, and FIG. 7F; optionally including a moiety of FIG.    4B, 4C, 4D, 4E or 4F or (ii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C,    3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C,    and 7F; optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F;    as described herein as described herein in substantially pure form    (e.g., at least 90 or 95%);-   (y) A compound that is prepared from or consists of moieties    selected from FIG. 1D or 1E; 5; 6A, 6B, or 6C; 7A, 7B, 7C, 7D or 7E;    and 8; optionally including a moiety of FIG. 4B, 4C, 4D, 4E or 4F;    as described herein, and pharmaceutically acceptable salts and    prodrugs thereof, for use in treating a medical disorder which is an    inflammatory or immune condition, a disorder mediated by the    complement cascade (including a dysfunctional cascade), a disorder    or abnormality of a cell that adversely affects the ability of the    cell to engage in or respond to normal complement activity, or an    undesired complement-mediated response to a medical treatment, such    as surgery or other medical procedure or a pharmaceutical or    biopharmaceutical drug administration, a blood transfusion, or other    allogenic tissue or fluid administration; and-   (z) A compound of that is prepared from or consists of moieties    selected from (i) any of FIG. 1B, 1C, 1D or 1E; FIG. 5; any one of    FIGS. 6A, 6B, 6C and FIG. 7F; optionally including a moiety of FIG.    4 (ii) FIGS. 1B, 1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I,    3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7F; optionally    including a moiety of FIG. 4B, 4C, 4D, 4E or 4F; or (iii) FIGS. 1B,    1C, 2B, 2C, 2D, 2E, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M,    3N, 3O, 3P, 3Q, 6A, 6B, 6C, and 7G; optionally including a moiety of    FIG. 4B, 4C, 4D, 4E or 4F; as described herein, and pharmaceutically    acceptable salts and prodrugs thereof, for use in treating a medical    disorder which is an inflammatory or immune condition, a disorder    mediated by the complement cascade (including a dysfunctional    cascade), a disorder or abnormality of a cell that adversely affects    the ability of the cell to engage in or respond to normal complement    activity, or an undesired complement-mediated response to a medical    treatment, such as surgery or other medical procedure or a    pharmaceutical or biopharmaceutical drug administration, a blood    transfusion, or other allogenic tissue or fluid administration.-   (aa) For each of (a) through (z) above, and otherwise herein, each    assembly of moieties in the Figures and each active compound made    therefrom or its use is considered and deemed specifically and    individually disclosed, as such depiction is for convenience of    space only and not intended to describe a only a genus or even a    subgenus for such indication.-   (bb) in another embodiment, any moiety of “A” (FIG. 1B, C, D or E);    any moiety of “B” ((FIG. 2B, C, D, or E), FIG. 7(A, B, C, D, E, F    or G) or FIG. 8); any moiety of the core ((FIG. 3B, C, D, E, F, G.    H, I, J, K, L, M. N, O, P or Q) or FIG. 5), any moiety of Linker    (FIG. 4B, C, D, E, F, or (i) and any moiety of R³² (FIG. 6A, B,    or C) can be combined to treat an indication of Section A; and the    assembly of moieties from the Figures and each active compound made    therefrom is considered and deemed specifically and individually    disclosed, as such depiction is for convenience of space only and    not intended to describe a only a genus or even a subgenus for such    indication;-   (cc) In another embodiment, any moiety of “A” (FIG. 1B, C, or F);    any moiety of “B” ((FIG. 2B, C, D, or E), FIG. 7(A, B, C, D, E, F    or G) or FIG. 8); any moiety of the core ((FIG. 3B, C, D, E, F, G,    H, I, J, K, L, M, N, O, P or Q) or FIG. 5), any moiety of Linker    (FIG. 4B, C, D, E, F, or G) and any moiety of R³² (FIG. 6A, B, or C)    can be combined to treat an indication of Section B with the proviso    that there is at least one moiety selected from FIG. 1(B, C, or F);    or FIG. 7F; FIG. 4F; or FIG. 6(C); and the assembly of moieties from    the Figures and each active compound made therefrom is considered    and deemed specifically and individually disclosed, as such    depiction is for convenience of space only and not intended to    describe a only a genus or even a subgenus for such indication.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is an illustration of Formula I which highlights the location ofthe A ring.

FIGS. 1B and 1C provide non-limiting embodiments of the A ring, whereinR³² is defined below.

FIGS. 1D, 1E, and 1F illustrate non-limiting embodiments of the A ringof FIG. 1A, wherein R⁴, R⁵, R⁶, R⁷, R⁸, R^(8′), R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁹, R³², X¹¹, X¹², X¹³, and X¹⁴ are defined below.

FIG. 2A illustrates the location of the B ring of Formula I.

FIGS. 2B, 2C, 2D and 2E provide certain embodiments of the B ring,wherein “halo” can be F, Cl, Br, or I.

FIG. 3A illustrates the location of the Central Core of Formula I.

FIGS. 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, and 3Qprovide non-limiting embodiments of the Central Core ring (C ring),wherein q is 0, 1, 2 or 3, r is 1, 2 or 3,

is a single or double bond, and R⁴⁴, R⁴⁴′, R⁴⁵, R⁴⁵′ are describedbelow; wherein each group can be optionally substituted.

FIG. 4A illustrates the location of the Linker in Formula I.

FIGS. 4B, 4C, 4D, 4E, 4F and 4G, provide non-limiting specificembodiments of the Linker (L), wherein R¹⁷, R¹⁸, R¹⁸′, and m are definedbelow.

FIG. 5 provides non-limiting specific embodiments of the Central Corering, wherein R, R′, and R³ are defined below.

FIGS. 6A, 6B, and 6C, provide non-limiting specific embodiments of R³².

FIGS. 7A, 7B, 7C, 7D, 7E, 7F and 7G provide non-limiting specificembodiments of the B ring, wherein R²⁷, R²⁸, and R²⁹ are defined below.

FIG. 8 provides non-limiting specific embodiments of the B ring.

FIGS. 9A, 9B, 9C, 9D, 9E, 9F, 9G and 9H provide non-limiting examples ofcompounds included in the present invention, wherein Z₃₂ is the same asR³² as used herein.

DETAILED DESCRIPTION I. Terminology

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein includeenantiomers, mixture of enantiomers, diasteromers, tautomers, racematesand other isomers, such as rotamers, as if each is specificallydescribed, unless otherwise indicated in the text or drawing orotherwise indicated in context. “Formula I” includes all subgenericgroups of Formula I, such as Formula IA and Formula IB and also includespharmaceutically acceptable salts of a compound of Formula I, unlessclearly contraindicated by the context in which this phrase is used.“Formula I” also includes all subgeneric groups of Formula I, such asFormulas IC-ID, and Formulas II-XXX, and also includes pharmaceuticallyacceptable salts of all subgeneric groups of Formula I, such as FormulasIA-ID, and Formulas II-XXX, unless contraindicated by the context inwhich this phrase is used.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed. Unless definedotherwise, technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The present invention includes compounds of Table 2 or an embodiment ofthe active compound as described in the Figures and the use of compoundsof Formula I, Table 1 and Table 2 or an embodiment of the activecompound as described in the Figures with at least one desired isotopicsubstitution of an atom, at an amount above the natural abundance of theisotope, i.e., enriched. Isotopes are atoms having the same atomicnumber but different mass numbers, i.e., the same number of protons buta different number of neutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I respectively. In one embodiment,isotopically labelled compounds can be used in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the schemes or in the examplesand preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures that achieves the desired result. Alternatively orin addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used. In oneembodiment, the isotopic substitution is deuterium for hydrogen at oneor more locations on the molecule to improve the performance of thedrug, for example, the pharmacodynamics, pharmacokinetics,biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. Forexample, the deuterium can be bound to carbon in a location of bondbreakage during metabolism (an α-deuterium kinetic isotope effect) ornext to or near the site of bond breakage (a β-deuterium kinetic isotopeeffect).

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one embodiments deuterium is 90, 95 or 99% enriched at adesired location. Unless otherwise stated, the enrichment at any pointis above natural abundance and enough to alter a detectable property ofthe drug in a human.

In one embodiment, the substitution of a hydrogen atom for a deuteriumatom can be provided in any of the A, B, L, or central core moieties. Inone embodiment, the substitution of a hydrogen atom for a deuterium atomoccurs within an R group selected from any of R^(1′), R², R^(2′), R³,R^(3′), R⁴, R⁵, R⁶, R^(6′), R⁷, R⁸, R^(8′), R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R^(18′), R¹⁹, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷,R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷ and R⁷⁵. For example,when any of R groups are, or contain for example through substitution,methyl, ethyl, or methoxy, the alkyl residue may be deuterated (innon-limiting embodiments, CD₃, CH₂CD₃, CD₂CD₃, CDH₂, CD₂H, CD₃, CHDCH₂D,CH₂CD₃, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃ etc.). In some embodiments, an Rgroup has a “′” or an “a” designation, which in one embodiment can bedeuterated. In certain other embodiments, when two substituents of thecentral core ring are combined to form a cyclopropyl ring, theunsubstituted methylene carbon may be deuterated.

The substitution of a hydrogen atom for a deuterium atom occurs withinan R group when at least one of the variables within the R group ishydrogen (e.g., ²H or D) or alkyl. For example, when any of R groupsare, or contain for example through substitution, methyl or ethyl, thealkyl residue may be deuterated (in non-limiting embodiments, CD₃,CH₂CD₃, CD₂CD₃, CDH₂, CD₂H, CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂, etc.).

The compound of the present invention may form a solvate with solvents(including water). Therefore, in one embodiment, the invention includesa solvated form of the active compound. The term “solvate” refers to amolecular complex of a compound of the present invention (including asalt thereof) with one or more solvent molecules. Non-limiting examplesof solvents are water, ethanol, dimethyl sulfoxide, acetone and othercommon organic solvents. The term “hydrate” refers to a molecularcomplex comprising a compound of the invention and water.Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO. A solvate can be in a liquidor solid form.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the keto (C═O) group.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a moietyselected from the indicated group, provided that the designated atom'snormal valence is not exceeded and the resulting compound is stable. Forexample, when the substituent is oxo (i.e., ═O) then two hydrogens onthe atom are replaced. For example a pyridyl group substituted by oxo isa pyridone. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds oruseful synthetic intermediates.

A stable active compound refers to a compound that can be isolated andcan be formulated into a dosage form with a shelf life of at least onemonth. A stable manufacturing intermediate or precursor to an activecompound is stable if it does not degrade within the period needed forreaction or other use. A stable moiety or substituent group is one thatdoes not degrade, react or fall apart within the period necessary foruse. Non-limiting examples of unstable moieties are those that combineheteroatoms in an unstable arrangement, as typically known andidentifiable to those of skill in the art.

Any suitable group may be present on a “substituted” or “optionallysubstituted” position that forms a stable molecule and meets the desiredpurpose of the invention and includes, but is not limited to, e.g.,halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl;nitro; azido; alkanoyl (such as a C₂-C₆ alkanoyl group); carboxamide;alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy;alkylthio including those having one or more thioether linkages;alkylsulfinyl; alkylsulfonyl groups including those having one or moresulfonyl linkages; aminoalkyl groups including groups having one or moreN atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ringeither substituted or unsubstituted aromatic); arylalkyl having forexample, 1 to 3 separate or fused rings and from 6 to about 14 or 18ring carbon atoms, with benzyl being an exemplary arylalkyl group;arylalkoxy, for example, having 1 to 3 separate or fused rings withbenzyloxy being an exemplary arylalkoxy group; or a saturated,unsaturated, or aromatic heterocyclic group having 1 to 3 separate orfused rings with one or more N, O or S atoms, e.g. coumarinyl,quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl,pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl,isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl,piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be furthersubstituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. Incertain embodiments “optionally substituted” includes one or moresubstituents independently selected from halogen, hydroxyl, amino,cyano, —CHO, —COOH, —CONH₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,—C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylester, (mono- anddi-C₁-C₆alkylamino)C₀-C₂alkyl, C₁-C₂haloalkyl, hydoxyC₁-C₆alkyl, ester,carbamate, urea, sulfonamide, —C₁-C₆alkyl(heterocyclo),C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(C₃-C₇cycloalkyl),O—C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂, phosphate, phosphonate andC₁-C₂haloalkoxy.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbongroup. In one embodiment, the alkyl contains from 1 to about 12 carbonatoms, more generally from 1 to about 6 carbon atoms or from 1 to about4 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8carbon atoms. In certain embodiments, the alkyl is C₁-C₂, C₁-C₃, orC₁-C₆. The specified ranges as used herein indicate an alkyl grouphaving each member of the range described as an independent species. Forexample, the term C₁-C₆ alkyl as used herein indicates a straight orbranched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and isintended to mean that each of these is described as an independentspecies. For example, the term C₁-C₄alkyl as used herein indicates astraight or branched alkyl group having from 1, 2, 3, or 4 carbon atomsand is intended to mean that each of these is described as anindependent species. When C₀-C_(n) alkyl is used herein in conjunctionwith another group, for example, (C₃-C₇cycloalkyl)C₀-C₄ alkyl, or—C₀-C₄alkyl(C₃-C₇cycloalkyl), the indicated group, in this casecycloalkyl, is either directly bound by a single covalent bond(C₀alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4carbon atoms. Alkyls can also be attached via other groups such asheteroatoms as in —O—C₀-C₄alkyl(C₃-C₇cycloalkyl). Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl,neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane,2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl. In one embodiment,the alkyl group is optionally substituted as described above.

In one embodiment, when a term is used that includes “alk” it should beunderstood that “cycloalkyl” or “carbocyclic” can be considered part ofthe definition, unless unambiguously excluded by the context. Forexample and without limitation, the terms alkyl, alkenyl, alkynyl,alkoxy, alkanoyl, alkenloxy, haloalkyl, aminoalkyl, alkylene,alkenylene, alkynylene, etc. can all be considered to include the cyclicforms of alkyl, unless unambiguously excluded by context.

“Alkenyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon double bonds that may occur at a stablepoint along the chain. Non-limiting examples are C₂-C₈alkenyl,C₂-C₆alkenyl and C₂-C₄alkenyl. The specified ranges as used hereinindicate an alkenyl group having each member of the range described asan independent species, as described above for the alkyl moiety.Examples of alkenyl include, but are not limited to, ethenyl andpropenyl. In one embodiment, the alkenyl group is optionally substitutedas described above.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain, for example, C₂-C₈alkynyl or C₂-C₆alkynyl.The specified ranges as used herein indicate an alkynyl group havingeach member of the range described as an independent species, asdescribed above for the alkyl moiety. Examples of alkynyl include, butare not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, the alkynyl groupis optionally substituted as described above.

“Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example,can be a 1 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicatednumber of carbon atoms, for example C₁-C₄alkylene, C₁-C₃alkylene, orC₁-C₂alkylene.

“Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbondouble bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkenylene.

“Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbontriple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkynylene.

“Alkoxy” is an alkyl group as defined above covalently bound through anoxygen bridge (—O—). Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy,n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy,2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly an “alkylthio” or a“thioalkyl” group is an alkyl group as defined above with the indicatednumber of carbon atoms covalently bound through a sulfur bridge (—S—).In one embodiment, the alkoxy group is optionally substituted asdescribed above.

“Alkenyloxy” is an alkenyl group as defined covalently bound to thegroup it substitutes by an oxygen bridge (—O—).

“Alkanoyl” is an alkyl group as defined above covalently bound through acarbonyl (C═O) bridge. The carbonyl carbon is included in the number ofcarbons, that is C₂alkanoyl is a CH₃(C═O)— group. In one embodiment, thealkanoyl group is optionally substituted as described above.

“Alkylester” is an alkyl group as defined herein covalently boundthrough an ester linkage. The ester linkage may be in eitherorientation, e.g., a group of the formula —O(C═O)alkyl or a group of theformula —(C═O)Oalkyl.

“Amide” or “carboxamide” is —C(O)NR^(a)R^(b) wherein R^(a) and R^(b) areeach independently selected from hydrogen, alkyl, for example,C₁-C₆alkyl, alkenyl, for example, C₂-C₆alkenyl, alkynyl, for example,C₂-C₆alkynyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkyl(C₃-C₇heterocycloalkyl), —C₀-C₄alkyl(aryl), and—C₀-C₄alkyl(heteroaryl); or together with the nitrogen to which they arebonded, R^(a) and R^(b) can form a C₃-C₇heterocyclic ring. In oneembodiment, the R^(a) and R^(b) groups are each independently optionallysubstituted as described above.

“Carbocyclic group”, “carbocyclic ring”, or “cycloalkyl” is a saturatedor partially unsaturated (i.e., not aromatic) group containing allcarbon ring atoms. A carbocyclic group typically contains 1 ring of 3 to7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms.Cycloalkyl substituents may be pendant from a substituted nitrogen orcarbon atom, or a substituted carbon atom that may have two substituentscan have a cycloalkyl group, which is attached as a spiro group.Examples of carbocyclic rings include cyclohexenyl, cyclohexyl,cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropylrings. In one embodiment, the carbocyclic ring is optionally substitutedas described above. In one embodiment, the cycloalkyl is a partiallyunsaturated (i.e., not aromatic) group containing all carbon ring atoms.In another embodiment, the cycloalkyl is a saturated group containingall carbon ring atoms.

“Carbocyclic-oxy group” is a monocyclic carbocyclic ring or a mono- orbi-cyclic carbocyclic group as defined above attached to the group itsubstitutes via an oxygen, —O—, linker.

“Haloalkyl” indicates both branched and straight-chain alkyl groupssubstituted with 1 or more halogen atoms, up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl include, but are notlimited to, trifluoromethyl, monofluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined herein attachedthrough an oxygen bridge (oxygen of an alcohol radical).

“Hydroxyalkyl” is an alkyl group as previously described, substitutedwith at least one hydroxyl substituent.

“Aminoalkyl” is an alkyl group as previously described, substituted withat least one amino substituent.

“Halo” or “halogen” indicates independently any of fluoro, chloro, bromoor iodo.

“Aryl” indicates an aromatic group containing only carbon in thearomatic ring or rings. In one embodiment, the aryl groups contain 1 to3 separate or fused rings and is 6 to about 14 or 18 ring atoms, withoutheteroatoms as ring members. When indicated, such aryl groups may befurther substituted with carbon or non-carbon atoms or groups. Suchsubstitution may include fusion to a 4 to 7 or a 5 to 7-memberedsaturated or partially unsaturated cyclic group that optionally contains1, or 3 heteroatoms independently selected from N, O, B, P, Si and/or S,to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groupsinclude, for example, phenyl and naphthyl, including 1-naphthyl and2-naphthyl. In one embodiment, aryl groups are pendant. An example of apendant ring is a phenyl group substituted with a phenyl group. In oneembodiment, the aryl group is optionally substituted as described above.

The term “heterocycle,” or “heterocyclic ring” as used herein refers toa saturated or a partially unsaturated (i.e., having one or more doubleand/or triple bonds within the ring without aromaticity) carbocyclicmoiety of 3 to about 12, and more typically 3, 5, 6, 7 to 10 ring atomsin which at least one ring atom is a heteroatom selected from nitrogen,oxygen, phosphorus and sulfur, the remaining ring atoms being C, whereone or more ring atoms is optionally substituted independently with oneor more substituents described above. A heterocycle may be a monocyclehaving 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatomsselected from N, O, P, and S) or a bicycle having 6 to 10 ring members(4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, andS), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. In oneembodiment, the only heteroatom is nitrogen. In one embodiment, the onlyheteroatom is oxygen. In one embodiment, the only heteroatom is sulfur.Heterocycles are described in Paquette, Leo A.; “Principles of ModernHeterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularlyChapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds,A series of Monographs” (John Wiley & Sons, New York, 1950 to present),in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.(1960) 82:5566. Examples of heterocyclic rings include, but are notlimited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl,homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl,oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, dihydroisoquinolinyl,tetrahydroisoquinolinyl, pyrazolidinylimidazolinyl, imidazolidinyl,2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane,8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane,2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl,quinolizinyl, N-pyridyl ureas, and pyrrolopyrimidine. Spiro moieties arealso included within the scope of this definition. Examples of aheterocyclic group wherein 1 or 2 ring carbon atoms are substituted withoxo (═O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. Theheterocycle groups herein are optionally substituted independently withone or more substituents described herein.

“Heterocyclicoxy group” is a monocyclic heterocyclic ring or a bicyclicheterocyclic group as described previously linked to the group itsubstitutes via an oxygen, —O—, linker.

“Heteroaryl” indicates a stable monocyclic aromatic ring which containsfrom 1 to 3, or in some embodiments from 1, 2 or 3 heteroatoms selectedfrom N, O, S, B or P with remaining ring atoms being carbon, or a stablebicyclic or tricyclic system containing at least one 4 to 7 or 5- to7-membered aromatic ring which contains from 1 to 3, or in someembodiments from 1 to 2, heteroatoms selected from N, O, S, B or P withremaining ring atoms being carbon. In one embodiment, the onlyheteroatom is nitrogen. In one embodiment, the only heteroatom isoxygen. In one embodiment, the only heteroatom is sulfur. Monocyclicheteroaryl groups typically have from 5 to 7 ring atoms. In someembodiments bicyclic heteroaryl groups are 9- to 10-membered heteroarylgroups, that is, groups containing 9 or 10 ring atoms in which one 5- to7-member aromatic ring is fused to a second aromatic or non-aromaticring. When the total number of S and O atoms in the heteroaryl groupexceeds 1, these heteroatoms are not adjacent to one another. In oneembodiment, the total number of S and O atoms in the heteroaryl group isnot more than 2. In another embodiment, the total number of S and Oatoms in the aromatic heterocycle is not more than 1. Examples ofheteroaryl groups include, but are not limited to, pyridinyl (including,for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl,pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.Heteroaryl groups are optionally substituted independently with one ormore substituents described herein. “Heteroaryloxy” is a heteroarylgroup as described bound to the group it substituted via an oxygen, —O—,linker.

“Heterocycloalkyl” is a saturated ring group. It may have, for example,1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, withremaining ring atoms being carbon. In a typical embodiment, nitrogen isthe heteroatom. Monocyclic heterocycloalkyl groups typically have from 3to about 8 ring atoms or from 4 to 6 ring atoms. Examples ofheterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl,and pyrrolinyl.

The term “mono- and/or di-alkylamino” indicate a secondary or tertiaryalkylamino group, wherein the alkyl groups are independently selectedalkyl groups, as defined herein. The point of attachment of thealkylamino group is on the nitrogen. Examples of mono- and di-alkylaminogroups include ethylamino, dimethylamino, and methyl-propyl-amino.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like. A “dosage form” canalso include an implant, for example an optical implant.

“Pharmaceutical compositions” are compositions comprising at least oneactive agent, and at least one other substance, such as a carrier.“Pharmaceutical combinations” are combinations of at least two activeagents which may be combined in a single dosage form or providedtogether in separate dosage forms with instructions that the activeagents are to be used together to treat any disorder described herein.

A “pharmaceutically acceptable salt” is a derivative of the disclosedcompound in which the parent compound is modified by making inorganicand organic, non-toxic, acid or base addition salts thereof. The saltsof the present compounds can be synthesized from a parent compound thatcontains a basic or acidic moiety by conventional chemical methods.Generally, such salts can be prepared by reacting free acid forms ofthese compounds with a stoichiometric amount of the appropriate base(such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are typical, where practicable.Salts of the present compounds further include solvates of the compoundsand of the compound salts.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like, or using a differentacid that produces the same counterion. Lists of additional suitablesalts may be found, e.g., in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term “carrier” applied to pharmaceutical compositions/combinationsof the invention refers to a diluent, excipient, or vehicle with whichan active compound is provided.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, non-toxic and neither biologically nor otherwiseinappropriate for administration to a host, typically a human. In oneembodiment, an excipient is used that is acceptable for veterinary use.

A “patient” or “host” or “subject” is a human or non-human animal inneed of treatment or prevention of any of the disorders as specificallydescribed herein, including but not limited to by modulation of thecomplement Factor D pathway. Typically the host is a human. A “patient”or “host” or “subject” also refers to for example, a mammal, primate(e.g., human), cows, sheep, goat, horse, dog, cat, rabbit, rat, mice,fish, bird and the like.

A “prodrug” as used herein, means a compound which when administered toa host in vivo is converted into a parent drug. As used herein, the term“parent drug” means any of the presently described chemical compoundsdescribed herein. Prodrugs can be used to achieve any desired effect,including to enhance properties of the parent drug or to improve thepharmaceutic or pharmacokinetic properties of the parent. Prodrugstrategies exist which provide choices in modulating the conditions forin vivo generation of the parent drug, all of which are deemed includedherein. Non-limiting examples of prodrug strategies include covalentattachment of removable groups, or removable portions of groups, forexample, but not limited to acylation, phosphorylation, phosphonylation,phosphoramidate derivatives, amidation, reduction, oxidation,esterification, alkylation, other carboxy derivatives, sulfoxy orsulfone derivatives, carbonylation or anhydride, among others.

“Providing a compound with at least one additional active agent,” forexample, in one embodiment can mean that the compound and the additionalactive agent(s) are provided simultaneously in a single dosage form,provided concomitantly in separate dosage forms, or provided in separatedosage forms for administration. In one embodiment, the compoundadministrations are separated by some amount of time that is within theblood stream of a patient. In certain embodiments the compound and theadditional active agent need not be prescribed for a patient by the samemedical care worker. In certain embodiments the additional active agentor agents need not require a prescription. Administration of thecompound or the at least one additional active agent can occur via anyappropriate route, for example, oral tablets, oral capsules, oralliquids, inhalation, injection, suppositories, parenteral, sublingual,buccal, intravenous, intraaortal, transdermal, polymeric controlleddelivery, non-polymeric controlled delivery, nano or microparticles,liposomes, and/or topical contact.

A “therapeutically effective amount” of a pharmaceuticalcomposition/combination of this invention means an amount effective,when administered to a host, to provide a therapeutic benefit such as anamelioration of symptoms or reduction or dimunition of the diseaseitself. In one embodiment, a therapeutically effective amount is anamount sufficient to prevent a significant increase or willsignificantly reduce the detectable level of complement Factor D in thepatient's blood, serum, or tissues.

II. Detailed Description of the Active Compounds

PCT Patent Application No. PCT/US2015/017538 and U.S. patent applicationSer. No. 14/631,233 titled “Amide Compounds for Treatment of ComplementMediated Disorders” defines a compound of Formula I as:

as well as the pharmaceutically acceptable salts and compositionsthereof. In one embodiment, the invention is the use of a compound ofFormula I, or a pharmaceutically acceptable salt or composition thereof,wherein R¹² or R¹³ on the A group is an amide substituent, includingthose compounds set out in Table 1, for the treatment of a disorder in ahost, typically a human, wherein the disorder is selected from the groupdisclosed in the Detailed Description, Part IV, Section A.

Formula I can be considered to have a central core, an L substituent, aB substituent (which can be an L-B substituent), and a (C═O)Asubstituent. Non-limiting examples of compounds falling within Formula Iwith variations in the variables e.g., A, B, R¹-R^(3′), the centralcore, and L, are illustrated below. The disclosure includes the use ofall combinations of these definitions so long as a stable compoundresults. In one embodiment, the compound of Formula I is selected fromthe compounds in Table 1 below.

in certain embodiments, any of the active compounds can be provided inits N-oxide form to a patient in need thereof. In a differentembodiment, an N-oxide of one of the active compounds or a precursor ofthe active compound is used in a manufacturing scheme. In yet anotherembodiment, the N-oxide is a metabolite of administration of one of theactive compounds herein, and may have independent activity. The N-oxidecan be formed by treating the compound of interest with an oxidizingagent, for example a suitable peroxyacid or peracid, to generate anN-oxide compound. For example, a heteroaryl group, for example a pyridylgroup, can be treated with an oxidizing agent such as sodiumpercarbonate in the presence of a rhenium-based catalyst under mildreaction conditions to generate an N-oxide compound. A person skilled inthe art will understand that appropriate protecting groups may benecessary to carry out the chemistry. See, Jain, S. L. et al.,“Rhenium-Catalyzed Highly Efficient Oxidations of Tertiary NitrogenCompounds to N-Oxides Using Sodium Percarbonate as Oxygen Source,Synlett, 2261-2663, 2006.

In one embodiment, a sulfur atom in a selected compound as describedherein can be oxidized to form a sulfoxide

or a sulfone

For example, the compound1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-tetrachloride (TAPC) is anefficient promoter for the oxidation of sulfides to sulfoxides. See,Bahrami, M. et al., “TAPC-Promoted Oxidation of sulfides andDeoxygenation of Sulfoxides”, J. Org. Chem., 75, 6208-6213 (2010).Oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalumcarbide provides sulfoxides in high yields, see, Kirihara, A., et al.,“Tantalum Carbide or Niobium Carbide Catalyzed Oxidation of Sulfideswith Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses ofSulfoxides and Sulfones”, Synlett, 1557-1561 (2010). Sulfides can beoxidized to sulfones using, for example, niobium carbide as thecatalyst, see, Kirihara, A., et al., “Tantalum Cardide or NiobiumCarbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: HighlyEfficient and Chemoselective Syntheses of Sulfoxides and Sulfones”,Synlett, 1557-1561 (2010). Urea-hydrogen peroxide adduct is a stableinexpensive and easily handled reagent for the oxidation of sulfides tosulfones, see Varma, R. S. and Naicker, K. P., “The Urea-HydrogenPeroxide Complex: Solid-State Oxidative Protocols for HydroxylatedAldehydes and Ketones (Dakin Reaction), Nitriles, Sulfides, and NitrogenHeterocycles”, Org. Lett., 1, 189-191 (1999). One skilled in the artwill appreciate that other heteroatoms, such as nitrogen, may need to beprotected and then deprotected while carrying out the oxidation of asulfur atom to produce the desired compound.Formulas II-XXX

In one aspect, the disclosure includes the use, as further describedherein, of a compound or salt of Formula II, III, IV, V, VI, VII, VIII,IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII,XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX and XXX. The variables shownin Formula II-XXX carry the definitions set forth in the SUMMARY sectionfor Formula I or any of the definitions set forth in this disclosure.

Additionally, the disclosure includes the use of compounds and salts ofFormula I and pharmaceutically acceptable compositions thereof, and anyof its subformulae (II-XXX) in which at least one of the followingconditions is met in the embodiments described below.

The R¹² and R¹³ Amide Substituents

In one embodiment, the invention is the use of a compound of Formula I,or a pharmaceutically acceptable salt or composition thereof, wherein atleast one of R¹² or R¹³ on the A group is an amide substituent,including those compounds set out in Table 1, for the treatment of adisorder in a host, typically a human, wherein the disorder is selectedfrom the group disclosed in the Detailed Description, Part IV, SectionA.

One of R¹² or R¹³ is R³². In one embodiment, one of R¹² and R¹³ isselected from R³¹ and the other of R¹² and R¹³ is selected from R³². Inan alternative embodiment, R¹² and R¹³ are each independently selectedfrom an R³² moiety.

R³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and —C(NR⁹)NR⁹R¹⁰, each ofwhich R³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy is unsubstituted or substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, amino, —COOH, —CONH₂C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,and each of which R³¹ is also optionally substituted with onesubstituent selected from phenyl and 4- to 7-membered heterocyclecontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS; which phenyl or 4- to 7-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl)(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, andC₁-C₂haloalkoxy;

R³² is selected from C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, and —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted.

In one embodiment, when R³² is C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, Bis not C₂-C₆ alkenyl; (C₀-C₄ alkyl)(heteroaryl); monocyclic or bicycliccarbocyclic; or monocyclic heterocyclic.

When A is an indole or indazole and X¹² is N, X¹³ is CR¹³ wherein R¹³ isR³².

When A is an indole or indazole and X¹³ is N, X¹² is CR¹², wherein R¹²is R³².

Non-limiting examples of R³² include the structures of FIGS. 6A and 6B.

Non-Limiting R¹²/R¹³ Embodiments

In one embodiment, R¹² is R³².

In one embodiment, R¹³ is R³².

In one embodiment, R¹² is R³², which is —C(O)NR²¹R³⁷.

In one embodiment, R¹² is R³², which is —C(O)NR²⁴R²⁵.

In one embodiment, R¹² is R³², which is —C(O)NR⁹R³⁷.

In one embodiment, R¹² is R³², which is —C(O)NR²¹SO₂R²².

In one embodiment, R¹² is R³², which is —NR⁹C(O)OR¹⁰.

In one embodiment, R¹² is R³², which is —NR⁹C(O)OR²³.

In one embodiment, R¹² is R³², which is —NR⁹C(O)R²¹.

In one embodiment, R¹² is R³², which is —NR⁹C(O)NR⁹R¹⁰.

In one embodiment, R¹² is R³², which is —NR⁹C(O)NR¹⁰R²³.

In one embodiment, R¹² is R³², which is —NR⁹C(O)NR²⁴R²⁵.

In one embodiment, R¹³ is R³², which is —C(O)NR²¹R³⁷.

In one embodiment, R¹³ is R³², which is —C(O)NR²⁴R²⁵.

In one embodiment, R¹³ is R³², which is —C(O)NR⁹R³⁷.

In one embodiment, R¹³ is R³², which is —C(O)NR²¹SO₂R²².

In one embodiment, R¹³ is R³², which is —NR⁹C(O)OR¹⁰.

In one embodiment, R¹³ is R³², which is —NR⁹C(O)OR²³.

In one embodiment, R¹³ is R³², which is —NR⁹C(O)R²¹.

In one embodiment, R¹³ is R³², which is —NR⁹C(O)NR⁹R¹⁰.

In one embodiment, R¹³ is R³², which is —NR⁹C(O)NR¹⁰R²³.

In one embodiment, R¹³ is R³², which is —NR⁹C(O)NR²⁴R²⁵.

In one embodiment, the disclosure provides compounds of Formula I,wherein; one of R¹² and R¹³ is H and the other of R¹² and R¹³ is R³²,where:

R³² is selected from C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, and —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted;

wherein R⁹, R¹⁰, R²¹, R²², R²³, R²⁴, R²⁵, and R³⁷ are as defined in thesummary section above.

In another embodiment, the disclosure provides compounds of Formula I,wherein;

R¹, R^(1′), R², and R^(3′) are all hydrogen;

R² is fluoro and R³ is hydrogen, —C₀-C₄alkyl(C₃-C₇cycloalkyl), or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁵ is hydrogen, halogen, or C₁-C₂alkyl;

R¹¹, R¹³, R¹⁴, and R¹⁵, if present, are independently selected at eachoccurrence from hydrogen, halogen, hydroxyl, amino, C₁-C₄alkyl,C₁-C₄alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₂alkylamino), trifluoromethyl,and trifluoromethoxy;

X¹² is CR¹²; and

R¹² is selected from C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, and —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted;

wherein R⁹, R¹⁰, R²¹, R²², R²³, R²⁴, R²⁵, and R³⁷ are as defined in thesummary section above.

In one embodiment, when R³² is C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, Bis not C₂-C₆ alkenyl; (C₀-C₄ alkyl)(heteroaryl); monocyclic or bicycliccarbocyclic; or monocyclic heterocyclic.

In one embodiment, the disclosure provides compounds of Formula I,wherein;

m is 0 or 1;

R² is halogen, R^(2′) is hydrogen or halogen, and R³ is hydrogen,halogen, —C₀-C₄alkyl(C₃-C₇cycloalkyl), or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁶ is —C(O)C₁-C₄alkyl, —C(O)NH₂, —C(O)CF₃, —C(O)(C₃-C₇cycloalkyl), or-ethyl(cyanoimino);

one of R¹² and R¹³ is selected from hydrogen, halogen, C₁-C₄alkyl,C₁-C₄alkoxy, trifluoromethyl, and trifluoromethoxy; the other of R¹² andR¹³ is R³², where

R³² is selected from C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, and —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted;

wherein R⁹, R¹⁰, R²¹, R²², R²³, R²⁴, R²⁵, and R³⁷ are as defined in thesummary section above.

In one embodiment, the disclosure provides compounds of Formula I,wherein;

one of R¹² and R¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy;and the other of R¹² and R¹³ is R³², where

R³² is selected from C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, and —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted;

wherein R⁹, R¹⁰, R²¹, R²², R²³, R²⁴, R²⁵, and R³⁷ are as defined in thesummary section above.

In one embodiment, R³² may be unsubstituted or substituted with one ormore substituents independently selected from halogen, hydroxyl, nitro,cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂, —P(O)(OH)₂,C₁-C₆alkyl, C₁-C₆alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino),C₁-C₆alkylester, C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

Central Core Moiety

The central core moiety in Formula I is illustrated below:

wherein:

Q¹ is N(R¹) or C(R¹R^(1′));

Q² is C(R²R^(2′)), C(R²R^(2′))—C(R²R^(2′)), S, O, N(R²) or C(R²R^(2′))O;

Q³ is N(R³), S, or C(R³R^(3′));

X¹ and X² are independently N, CH, or CZ, or X¹ and X² together are C═C;and

wherein Q¹, Q², Q³, X¹, and X² are selected such that a stable compoundresults.

Any of the structures illustrated herein, e.g., A, B, L or central corecan be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, andindependently, selected from R⁷⁵, wherein R⁷⁵ is selected from hydrogen,halogen, hydroxyl, nitro, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆thioalkyl, C₁-C₆alkoxy,-JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)NR²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋OC(O)R²¹,-JC(O)OR²³; SC₁-C₆alkyl(O)═NH; each of which R⁷⁵ may be unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH,—CONH₂, —P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₆alkoxy, —C₀-C₄alkyl(mono- and)di-C₁-C₄alkylNR⁹R¹⁰, C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,—OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, S(O)═NHR²¹, SF₅, and JC(R⁹)═NR²¹and SO₂OR²¹.

Non-limiting examples of the

ring are illustrated in FIG. 5 (any of which can be otherwisesubstituted with R¹, R^(1′), R², R^(2′), R³, and R^(3′)).

In an alternate embodiment, the

ring is replaced by one of the following core structures:

wherein q is 0, 1, 2 or 3, r is 1, 2 or 3,

is a single or double bond.

It is clear that when q is 0,

is not a double bond.

Any of the structures illustrated herein, e.g., A, B, L or central corecan be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, andindependently, selected from R⁷⁵, wherein R⁷⁵ is selected from hydrogen,halogen, hydroxyl, nitro, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆thioalkyl, C₁-C₆alkoxy,-JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², JC(O)NR²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,-JC(O)OR²³; SC₁-C₆alkyl(O)═NH; each of which R⁷⁵ may be unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH,—CONH₂, —P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₆alkoxy, —C₀-C₄alkyl(mono- and di-C₁-C₄alkylNR⁹R¹⁰),C₁-C₆alkylester, C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰,—NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, S(O)═NHR²¹, SF₅, andJC(R⁹)═NR²¹ and SO₂OR²¹.

R and R′ are independently selected from H, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, aralkyl,heteroaryl, heteroarylalkyl wherein each group can be optionallysubstituted or any other substituent group herein that provides thedesired properties. In some embodiments, the ring includes one or morechiral carbon atoms. The invention includes embodiments in which thechiral carbon can be provided as an enantiomer, or mixtures ofenantiomers, including a racemic mixture. Where the ring includes morethan one stereocenter, all of the enantiomers and diastereomers areincluded in the invention as individual species.

Z is F, Cl, NH₂, CH₃, CH₂D, CHD₂, or CD₃.

R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently selected ateach occurrence, as appropriate, and only where a stable compoundresults, from hydrogen, halogen, hydroxyl, nitro, cyano, amino,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkynyl,C₂-C₆alkanoyl, C₁-C₆thioalkyl, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl,—C₀-C₄alkylNR⁹R¹⁰, —C(O)OR⁹, —OC(O)OR⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰,—OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, whereR⁹ and R¹⁰ are independently selected at each occurrence from hydrogen,C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl).

Examples of central cores include, but are not limited to:

R¹⁰¹ is C₁-C₄ alkyl or C₃-C₇ cycloalkyl.

R¹⁰² is C₁-C₄ alkyl, fluorine, chlorine, or bromine.

Non-Limiting Central Core Embodiments

In alternative embodiments, R¹ and R^(1′) or R³ and R^(3′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring or a 3- to6-membered heterocyclic spiro ring containing 1 or 2 heteroatomsindependently selected from N, O, or S; R² and R^(2′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring; or R² andR^(2′) may be taken together to form a 3- to 6-membered heterocyclicspiro ring; each of which ring may be unsubstituted or substituted with1 or more substituents independently selected from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In alternative embodiments, R¹ and R² may be taken together to form a3-membered carbocyclic ring; R¹ and R² may be taken together to form a4- to 6-membered carbocyclic or aryl ring or a 4- to 6-memberedheterocyclic or heteroaryl ring containing 1 or 2 heteroatomsindependently selected from N, O, and S; or R² and R³, if bound toadjacent carbon atoms, may be taken together to form a 3- to 6-memberedcarbocyclic or aryl ring or a 3- to 6-membered heterocyclic orheteroaryl ring; each of which ring may be unsubstituted or substitutedwith 1 or more substituents independently selected from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one embodiment, the central core moiety is proline.

In one embodiment, the central core moiety is 4-fluoroproline.

In one embodiment, R¹, R^(1′), R^(2′), R³, and R^(3′), if present, areall hydrogen; and R² is fluoro.

In one embodiment, R¹, R^(1′), R^(2′), and R^(3′), if present, are allhydrogen; and R² is fluoro and R³ is —C₀-C₄alkyl(C₃-C₇cycloalkyl) or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl).

In one embodiment, R¹ and R² are taken together to form a 3- to6-membered cycloalkyl group, and R^(1′), R^(2′), R³, and R^(3′), wherepresent, are all hydrogen.

In one embodiment, R¹, R^(1′), R³, and R^(3′), if present, are allhydrogen, and R² and R^(2′) are taken together to form a 5- or6-membered heterocycloalkyl group having 1 or 2 oxygen atoms.

In one embodiment, R¹ is hydrogen and R² is fluoro.

In one embodiment, R¹ and R² are joined to form a 3 membered ring.

The disclosure includes the use of compounds of Formula I in which thecentral pyrrolidine is vinyl substituted, for example:

In one embodiment, the compound of Formula I has the structure:

In one embodiment, the central pyrrolidine is modified by addition of asecond heteroatom to a pyrrolidine ring, such as N, O, S, Si, or B, forexample:

Another modification within the scope of the disclosure is joining asubstituent on the central pyrrolidine ring to R⁷ or R⁸ to form a 5- to6-membered heterocyclic ring, for example:

Example compounds having the modifications disclosed above include:

Central Core L-B Substituents

The central core L substituents and B substituents in Formula I areillustrated below:

L is a bond or is selected from the formulas:

where R¹⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl) andR¹⁸ and R^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicycliccarbocyclicoxy group; a monocyclic, bicyclic, or tricyclic heterocyclicgroup having 1, 2, 3, or 4 heteroatoms independently selected from N, O,and S and from 4 to 7 ring atoms per ring; C₂-C₆alkenyl; C₂-C₆alkynyl;—(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl).

Each of which B is unsubstituted or substituted with one or moresubstituents independently selected from R³³ and R³⁴, and 0 or 1substituents selected from R³⁵ and R³⁶:

R³³ is independently selected from halogen, hydroxyl, —COOH, cyano,C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R³⁴ is independently selected from nitro, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)NR²², -JC(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)NR²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,and -JC(O)OR²³; each of which R³⁴ may be unsubstituted or substitutedwith one or more substituents independently selected from halogen,hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂,—P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy,—C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy;

R³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4-to 7-membered heterocycloalkyl)C₀-C₄alkyl containing 1 or 2 heteroatomsselected from N, O, and S, and bicyclic heterocycle containing 1, 2, or3 heteroatoms independently selected from N, O, and S, and containing 4-to 7-ring atoms in each ring; each of which R³⁵ is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy; and

R³⁶ is independently selected from tetrazolyl, (phenyl)C₀-C₂alkyl,(phenyl)C₁-C₂alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently selected from N, O, B, and S, eachof which R³⁶ is unsubstituted or substituted with one or moresubstituents independently selected from halogen, hydroxyl, nitro,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, —OSi(CH₃)₂C(CH₃)₃,—Si(CH₃)₂C(CH₃)₃, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

J is independently selected at each occurrence from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene.

Examples of B moieties include, but are not limited to

Non-Limiting L-B Embodiments

In one embodiment, -L-B— is

where

-   R²⁶ and R²⁷ are independently selected from hydrogen, halogen,    hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,    C₁-C₆alkoxy, C₁-C₆thioalkyl, —C₀-C₄alkyl(mono- and    di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),    —C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and    C₁-C₂haloalkylthio.

In another embodiment, -L-B— is

wherein

R¹⁸ and R^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0 or 1; and

R²⁶, R²⁷, and R²⁸ are independently selected from hydrogen, halogen,hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,C₁-C₆alkoxy, C₁-C₆thioalkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl-, (heteroaryl)C₀-C₄alkyl-,and —C₀-C₄alkoxy(C₃-C₇cycloalkyl); each of which R²⁶, R²⁷, and R²⁸ otherthan hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, amino, C₁-C₂alkoxy, C₁-C₂haloalkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl-, and C₁-C₂haloalkoxy; and

R²⁹ is hydrogen, C₁-C₂alkyl, C₁C₂haloalkyl or —Si(CH₃)₂C(CH₃)₃.

In one embodiment, m is 0.

In one embodiment, the disclosure further includes the use of compoundsand salts of Formula I in which B is 2-fluoro-3-chlorophenyl. In anotherembodiment, another carbocyclic, aryl, heterocyclic, or heteroaryl groupsuch as 2-bromo-pyridin-6-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl,2,2-dichlorocyclopropylmethyl, or 2-fluoro-3-trimethylsilylphenyl isused.

In another embodiment, B is phenyl, pyridyl, or indanyl each of which isunsubstituted or substituted with one or more substituents independentlyselected from hydrogen, halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkoxy(C₃-C₇cycloalkyl), (phenyl)C₀-C₂alkyl, (pyridyl)C₀-C₂alkyl;each of which substituents other than hydrogen, halogen, hydroxyl,nitro, cyano, is unsubstituted or substituted with one or moresubstituents independently selected from halogen, hydroxyl, amino,C₁-C₂alkyl, C₁-C₂alkoxy, —OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In another embodiment, B is phenyl or pyridyl substituted with 1, 2, or3 substituents selected from chloro, bromo, hydroxyl, —SCF₃, C₁-C₂alkyl,C₁-C₂alkoxy, trifluoromethyl, phenyl and trifluoromethoxy each of whichsubstituents other than chloro, bromo, hydroxyl, —SCF₃, can beoptionally substituted.

In certain embodiments, B is a 2-fluoro-3-chlorophenyl or a2-fluoro-3-trifluoromethoxyphenyl group.

In one embodiment, B is pyridyl, optionally substituted with halogen,C₁-C₂alkoxy, and trifluoromethyl.

In one embodiment, B is phenyl, substituted with 1, 2, or 3 substituentsindependently selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,trifluoromethyl, and optionally substituted phenyl.

In one embodiment, R²³ is independently selected at each occurrence from(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S.

In one embodiment, B is selected from the structures of FIGS. 7A, 7B,7C, 7D, and 7E, wherein R²⁷ is hydrogen, methyl, or trifluoromethyl; R²⁸is hydrogen or halogen; and R²⁹ is hydrogen, methyl, trifluoromethyl, or—Si(CH₃)₂C(CH₃)₃.

In an alternative embodiment, B is selected from the structures of FIG.8.

Central Core (C═O)A Substituent

The central core (C═O)A substituent in Formula I is illustrated below:

A is a group selected from:

R⁴ is selected from —CHO, —CONH₂, C₂-C₆alkanoyl, hydrogen, —SO₂NH₂,—C(CH₂)₂F, —CH(CF₃)NH₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₂alkyl(C₃-C₇cycloalkyl),

each of which R⁴ other than hydrogen, —CHO, and —CONH₂, is unsubstitutedor substituted with one or more of amino, imino, halogen, hydroxyl,cyano, cyanoimino, C₁-C₂alkyl, C₁-C₂alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R⁵ and R⁶ are independently selected from —CHO, —C(O)NH₂, —C(O)NH(CH₃),C₂-C₆alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH,—SO₂NH₂, vinyl, C₁-C₆alkyl (including methyl), C₂-C₆alkenyl,C₁-C₆alkoxy, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl), —P(O)(OR⁹)₂, —OC(O)R⁹, —C(O)OR⁹,—C(O)N(CH₂CH₂R⁹)(R¹⁰), —NR⁹C(O)R¹⁰, phenyl, or 5- to 6-memberedheteroaryl.

Each R⁵ and R⁶ other than hydrogen, hydroxyl, cyano, and —COOH isunsubstituted or optionally substituted. For example, R⁵ and R⁶ otherthan hydrogen, hydroxyl, cyano, and —COOH may be substituted with one ormore substituents independently selected from halogen, hydroxyl, amino,imino, cyano, cyanoimino, C₁-C₂alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R^(6′) is hydrogen, halogen, hydroxyl, C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), or C₁-C₄alkoxy; or R⁶ and R^(6′) may betaken together to form an oxo, vinyl, or imino group.

R⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl).

R⁸ and R^(8′) are independently selected from hydrogen, halogen,hydroxyl, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) can be taken together with the carbonthat they are bonded to form a 3-membered carbocyclic ring.

R¹⁶ is absent or may include one or more substituents independentlyselected from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R¹⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,—SO₂C₁-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(C₃-C₇heterocycloalkyl),—C₀-C₄alkyl(aryl), C₀-C₄alkyl(heteroaryl), and wherein R¹⁹ other thanhydrogen is unsubstituted or substituted with one or more substituentsindependently selected from halogen, hydroxyl, amino, —COOH, and—C(O)OC₁-C₄alkyl.

X¹¹ is N or CR¹¹.

X¹² is N or CR¹².

X¹³ is N or CR¹³.

X¹⁴ is N or CR¹⁴.

No more than 2 of X¹¹, X¹², X¹³, and X¹⁴ are N.

R¹¹, R¹⁴, and R¹⁵ are independently selected at each occurrence fromhydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₂-C₆alkenyl(aryl),C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), C₂-C₆alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one embodiment, R⁵ and R⁶ are independently selected from —CHO,—C(O)NH₂, —C(O)NH(CH₃), C₂-C₆alkanoyl, and hydrogen.

In one embodiment, each R⁵ and R⁶ other than hydrogen, hydroxyl, cyano,and —COOH is unsubstituted or substituted with one or more substituentsindependently selected from halogen, hydroxyl, amino, imino, cyano,cyanoimino, C₁-C₂alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one embodiment, R⁸ and R^(8′) are independently hydrogen or methyl.

In one embodiment, R⁸ and R^(8′) are hydrogen.

In one embodiment, R⁷ is hydrogen or methyl.

In one embodiment, R⁷ is hydrogen.

Embodiments of Formulas IA, IB, IC, and ID

To further illustrate the invention, various embodiments of Formula IA,IB, IC and ID are provided. These are presented by way of example toshow some of the variations among presented compounds to be used withinthe invention and can be applied to any of the Formulas I-XXX.

In one aspect, this disclosure includes the use of compounds and saltsof Formula IA:

where

-   R⁶, R¹³, and B may carry any of the definitions set forth herein for    this variable.

In another aspect, this disclosure includes the use of compounds andsalts of Formula IB, IC, and ID.

In Formulas IA, IB, IC, and ID, the variables may include any of thedefinitions set forth herein that results in a stable compound. Incertain embodiments, the following conditions apply for Formula IB andIC.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ is H, R² is F, R⁶ isalkanoyl, R¹² is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, R¹³ is H, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ and R² are joined to forma 3 membered ring, R⁶ is alkanoyl, R¹² is R³², R³² is —C(O)NR²¹R³⁷,—C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³,—NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, eachof which is optionally substituted, R¹³ is H, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ is H, R² is F, R⁶ isamide, R¹² is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, R¹³ is H, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ and R² are joined to forma 3 membered ring, R⁶ is amide, R¹² is R³², R³² is —C(O)NR²¹R³⁷,—C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³,—NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, eachof which is optionally substituted, R¹³ is H, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ is H, R² is F, R⁶ isalkanoyl, R¹² is H, R¹³ is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵,—C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ and R² are joined to forma 3 membered ring, R⁶ is alkanoyl, R¹² is H, R¹³ is R³², R³² is—C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or—NR⁹C(O)NR²⁴R²⁵, each of which is optionally substituted, and B isheteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ is H, R² is F, R⁶ isamide, R¹² is H, R¹³ is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵,—C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ and R² are joined to forma 3 membered ring, R⁶ is amide, R¹² is H, R¹³ is R³², R³² is—C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or—NR⁹C(O)NR²⁴R²⁵, each of which is optionally substituted, and B isheteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ is H, R² is F, R⁶ isalkanoyl, R¹² is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, R¹³ is H, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ and R² are joined to forma 3 membered ring, R⁶ is alkanoyl, R¹² is R³², R³² is —C(O)NR²¹R³⁷,—C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³,—NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, eachof which is optionally substituted, R¹³ is H, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ is H, R² is F, R⁶ isamide, R¹² is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, R¹³ is H, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ and R² are joined to forma 3 membered ring, R⁶ is amide, R¹² is R³², R³² is —C(O)NR²¹R³⁷,—C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³,—NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, eachof which is optionally substituted, R¹³ is H, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ is H, R² is F, R⁶ isalkanoyl, R¹² is H, R¹³ is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵,—C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ and R² are joined to forma 3 membered ring, R⁶ is alkanoyl, R¹² is H, R¹³ is R³², R³² is—C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or—NR⁹C(O)NR²⁴R²⁵, each of which is optionally substituted, and B isphenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ is H, R² is F, R⁶ isamide, R¹² is H, R¹³ is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵,—C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=0, R¹ and R² are joined to forma 3 membered ring, R⁶ is amide, R¹² is H, R¹³ is R³², R³² is—C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or—NR⁹C(O)NR²⁴R²⁵, each of which is optionally substituted, and B isphenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ is H, R² is F, R⁶ isalkanoyl, R¹² is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, R¹³ is H, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ and R² are joined to forma 3 membered ring, R⁶ is alkanoyl, R¹² is R³², R³² is —C(O)NR²¹R³⁷,—C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³,—NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, eachof which is optionally substituted, R¹³ is H, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ is H, R² is F, R⁶ isamide, R¹² is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, R¹³ is H, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ and R² are joined to forma 3 membered ring, R⁶ is amide, R¹² is R³², R³² is —C(O)NR²¹R³⁷,—C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³,—NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, eachof which is optionally substituted, R¹³ is H, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ is H, R² is F, R⁶ isalkanoyl, R¹² is H, R¹³ is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵,—C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ and R² are joined to forma 3 membered ring, R⁶ is alkanoyl, R¹² is H, R¹³ is R³², R³² is—C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or—NR⁹C(O)NR²⁴R²⁵, each of which is optionally substituted, and B isheteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ is H, R² is F, R⁶ isamide, R¹² is H, R¹³ is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵,—C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, and B is heteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ and R² are joined to forma 3 membered ring, R⁶ is amide, R¹² is H, R¹³ is R³², R³² is—C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or—NR⁹C(O)NR²⁴R²⁵, each of which is optionally substituted, and B isheteroaryl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ is H, R² is F, R⁶ isalkanoyl, R¹² is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, R¹³ is H, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ and R² are joined to forma 3 membered ring, R⁶ is alkanoyl, R¹² is R³², R³² is —C(O)NR²¹R³⁷,—C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³,—NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, eachof which is optionally substituted, R¹³ is H, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ is H, R² is F, R⁶ isamide, R¹² is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷,—C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, R¹³ is H, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ and R² are joined to forma 3 membered ring, R⁶ is amide, R¹² is R³², R³² is —C(O)NR²¹R³⁷,—C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³,—NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, eachof which is optionally substituted, R¹³ is H, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ is H, R² is F, R⁶ isalkanoyl, R¹² is H, R¹³ is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵,—C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ and R² are joined to forma 3 membered ring, R⁶ is alkanoyl, R¹² is H, R¹³ is R³², R³² is—C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or—NR⁹C(O)NR²⁴R²⁵, each of which is optionally substituted, and B isphenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ is H, R² is F, R⁶ isamide, R¹² is H, R¹³ is R³², R³² is —C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵,—C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or —NR⁹C(O)NR²⁴R²⁵, each of which isoptionally substituted, and B is phenyl.

In some embodiments, uses of compounds are provided, as describedherein, comprising the administration of an effective amount of acompound of Formula IB or IC, wherein m=1, R¹ and R² are joined to forma 3 membered ring, R⁶ is amide, R¹² is H, R¹³ is R³², R³² is—C(O)NR²¹R³⁷, —C(O)NR²⁴R²⁵, —C(O)NR⁹R³⁷, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, or—NR⁹C(O)NR²⁴R²⁵, each of which is optionally substituted, and B isphenyl.

Embodiments of Formula VII

To further illustrate the invention, various embodiments of Formula VIIare provided that can be used as further described in this application.In one aspect, the disclosure includes uses, as described herein, ofcompounds and salts of Formula VII:

wherein:

R¹, R², R^(2′), and R³ are independently selected from hydrogen,halogen, C₁-C₄alkyl, C₁-C₄alkoxy, —C₀-C₂alkylNR⁹R¹⁰,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R⁸ and R^(8′) are independently selected from hydrogen, halogen, andmethyl;

R⁵ is hydrogen, hydroxyl, cyano, —COOH, C₁-C₆alkyl, C₁-C₆alkoxy,C₂-C₆alkanoyl —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl, C₁-C₂haloalkyl, or C₁-C₂haloalkoxy;

R⁶ is —C(O)CH₃, —C(O)NH₂, —C(O)CF₃, —C(O)(cyclopropyl), or-ethyl(cyanoimino); and

R¹¹ and R¹⁴ are independently selected from hydrogen, halogen, hydroxyl,amino, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,C₁-C₆alkoxy, C₁-C₆thioalkyl, —C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), —OC₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

Non-limiting examples of compounds of the invention provided hereininclude the structures of FIGS. 9A, 9B, 9C, 9D, 9E, 9F, 9G, and 9H.

The use of prodrugs of Formula I and Table 1 for the treatment of adisorder in a host, typically a human, wherein the disorder is selectedfrom the group disclosed in the Detailed Description, Part IV, Section Aare within the scope of the disclosure. Prodrugs of compounds selectedfrom Table 2 or an embodiment of the active compound as described in theFigures are also within the scope of the disclosure. The use of prodrugsof compounds selected from Table 2 or an embodiment of the activecompound as described in the Figures for the treatment of a disorder ina host, typically a human, wherein the disorder is selected from thegroup disclosed in the Detailed Description, Part IV, Section A andSection B, are also within the scope of the disclosure.

III. Pharmaceutical Preparations

Active compounds described herein can be administered to a host in needthereof as the neat chemical, but are more typically administered as apharmaceutical composition that includes an effective amount for a host,typically a human, in need of such treatment of an active compound asdescribed herein or its pharmaceutically acceptable salt. Thus, in oneembodiment, the disclosure provides pharmaceutical compositionscomprising an effective amount of compound or pharmaceuticallyacceptable salt together with at least one pharmaceutically acceptablecarrier for any of the uses described herein. The pharmaceuticalcomposition may contain a compound or salt as the only active agent, or,in an alternative embodiment, the compound and at least one additionalactive agent.

An effective amount of an active compound as described herein, or theactive compound described herein in combination or alternation with, orpreceded by, concomitant with or followed by another active agent, canbe used in an amount sufficient to (a) inhibit the progression of adisorder mediated by the complement pathway, including an inflammatory,immune, including an autoimmune, disorder or complement Factor D relateddisorder; (b) cause a regression of an inflammatory, immune, includingan autoimmune, disorder or complement Factor D related disorder; (c)cause a cure of an inflammatory, immune, including an autoimmune,disorder or complement Factor D related disorder; or inhibit or preventthe development of an inflammatory, immune, including an autoimmune,disorder or complement Factor D related disorder.

The exact amount of the active compound or pharmaceutical compositiondescribed herein to be delivered to the host, typically a human, in needthereof, will be determined by the health care provider to achieve thedesired clinical benefit.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10 mgto about 1000 mg, from about 100 mg to about 800 mg, or from about 200mg to about 600 mg of the active compound and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form. Examples are dosage formswith at least about 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, 750,800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, or 1700 mg of activecompound, or its salt. In one embodiment, the dosage form has at leastabout 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600mg of active compound, or its salt. The amount of active compound in thedosage form is calculated without reference to the salt. The dosage formcan be administered, for example, once a day (q.d.), twice a day(b.i.d.), three times a day (t.i.d.), four times a day (q.i.d.), onceevery other day (Q2d), once every third day (Q3d), as needed, or anydosage schedule that provides treatment of a disorder described herein.

The pharmaceutical composition may for example include any molar ratioof the active compound and additional active agent that achieves thedesired result. For example, the pharmaceutical composition may containa molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or fromabout 1.5:1 to about 4:1 of an additional active agent in combinationwith the active compound (additional active agent:active compound), orits salt, described herein. In one embodiment, the additional activeagent is an anti-inflammatory or immunosuppressing agent.

Compounds disclosed herein or used as described herein may beadministered orally, topically, parenterally, by inhalation or spray,sublingually, via implant, including ocular implant, transdermally, viabuccal administration, rectally, as an ophthalmic solution, injection,including ocular injection, intravenous, intra-aortal, intracranial,subdermal, intraperitoneal, subcutaneous, transnasal, sublingual,intrathecal, or rectal or by other means, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers. For oculardelivery, the compound can be administered, as desired, for example, asa solution, suspension, or other formulation via intravitreal,intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar,peribulbar, suprachorodial, subchorodial, chorodial, conjunctival,subconjunctival, episcleral, periocular, transscleral, retrobulbar,posterior juxtascleral, circumcorneal, or tear duct injections, orthrough a mucus, mucin, or a mucosal barrier, in an immediate orcontrolled release fashion or via an ocular device, injection, ortopically administered formulation, for example a solution or suspensionprovided as an eye drop.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a gel cap, a pill, amicroparticle, a nanoparticle, an injection or infusion solution, acapsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, adry powder, an inhalation formulation, in a medical device, suppository,buccal, or sublingual formulation, parenteral formulation, or anophthalmic solution or suspension. Some dosage forms, such as tabletsand capsules, are subdivided into suitably sized unit doses containingappropriate quantities of the active components, e.g., an effectiveamount to achieve the desired purpose.

Pharmaceutical compositions, and methods of manufacturing suchcompositions, suitable for administration as contemplated herein areknown in the art. Examples of known techniques include, for example,U.S. Pat. Nos. 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269,5,858,411, 6,254,889, 6,303,148, 6,395,302, 6,497,903, 7,060,296,7,078,057, 7,404,828, 8,202,912, 8,257,741, 8,263,128, 8,337,899,8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and9,387,252, incorporated by reference herein.

The pharmaceutical compositions contemplated here can optionally includea carrier. Carriers must be of sufficiently high purity and sufficientlylow toxicity to render them suitable for administration to the patientbeing treated. The carrier can be inert or it can possess pharmaceuticalbenefits of its own. The amount of carrier employed in conjunction withthe compound is sufficient to provide a practical quantity of materialfor administration per unit dose of the compound. Classes of carriersinclude, but are not limited to binders, buffering agents, coloringagents, diluents, disintegrants, emulsifiers, fillers, flavorants,glidents, lubricants, pH modifiers, preservatives, stabilizers,surfactants, solubilizers, tableting agents, and wetting agents. Somecarriers may be listed in more than one class, for example vegetable oilmay be used as a lubricant in some formulations and a diluent in others.Exemplary pharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Examples of other matrix materials, fillers, or diluents includelactose, mannitol, xylitol, microcrystalline cellulose, calciumdiphosphate, and starch. Examples of surface active agents includesodium lauryl sulfate and polysorbate 80. Examples of drug complexingagents or solubilizers include the polyethylene glycols, caffeine,xanthene, gentisic acid and cylodextrins. Examples of disintegrantsinclude sodium starch gycolate, sodium alginate, carboxymethyl cellulosesodium, methyl cellulose, colloidal silicon dioxide, and croscarmellosesodium. Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth. Examplesof lubricants include magnesium stearate and calcium stearate. Examplesof pH modifiers include acids such as citric acid, acetic acid, ascorbicacid, lactic acid, aspartic acid, succinic acid, phosphoric acid, andthe like; bases such as sodium acetate, potassium acetate, calciumoxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calciumhydroxide, aluminum hydroxide, and the like, and buffers generallycomprising mixtures of acids and the salts of said acids. Optional otheractive agents may be included in a pharmaceutical composition, which donot substantially interfere with the activity of the compound of thepresent invention.

In certain embodiments, the pharmaceutical composition foradministration further includes an active compound as described hereinand optionally comprises one or more of a phosphoglyceride;phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC);dioleylphosphatidyl ethanolamine (DOPE);dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine;cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate;diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such aspolyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surfaceactive fatty acid, such as palmitic acid or oleic acid; fatty acid;fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide;sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate(Span®20); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60);polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85(Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; asorbitan fatty acid ester such as sorbitan trioleate; lecithin;lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin;phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid;cerebroside; dicetylphosphate; dipalmitoylphosphatidylglycerol;stearylamine; dodecylamine; hexadecyl-amine; acetyl palmitate; glycerolricinoleate; hexadecyl sterate; isopropyl myristate; tyloxapol;poly(ethylene glycol)5000-phosphatidylethanolamine; poly(ethyleneglycol)400-monostearate; phospholipid; synthetic and/or naturaldetergent having high surfactant properties; deoxycholate; cyclodextrin;chaotropic salt; ion pairing agent; glucose, fructose, galactose,ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose,xylose, arabinose, glucoronic acid, galactoronic acid, mannuronic acid,glucosamine, galatosamine, and neuramic acid; pullulan, cellulose,microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC),hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran,glycogen, hydroxyethyl starch, carageenan, glycon, amylose, chitosan,N,O-carboxylmethylchitosan, algin and alginic acid, starch, chitin,inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid,curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol,and lactitol, a pluronic polymer, polyethylene, polycarbonate (e.g.poly(1,3-dioxan-2one)), polyanhydride (e.g. poly(sebacic anhydride)),polypropylfumerate, polyamide (e.g. polycaprolactam), polyacetal,polyether, polyester (e.g., polylactide, polyglycolide,polylactide-co-glycolide, polycaprolactone, polyhydroxyacid (e.g.poly((β-hydroxyalkanoate))), poly(orthoester), polycyanoacrylate,polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate,polymethacrylate, polyurea, polystyrene, and polyamine, polylysine,polylysine-PEG copolymer, and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol,Vitamin E TPGS (also known as d-α-Tocopheryl polyethylene glycol 1000succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP),hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC),methyl cellulose (MC), block copolymers of ethylene oxide and propyleneoxide (PEO/PPO), polyethyleneglycol (PEG), sodium carboxymethylcellulose(NaCMC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS).

In some embodiments, the pharmaceutical preparation may include apolymer for controlled delivery of the described compounds, including,but not limited to, a pluronic polymer, polyester (e.g., polylacticacid, poly(lactic-co-glycolic acid), polycaprolactone,polyvalerolactone, poly(1,3-dioxan-2one)); polyanhydride (e.g.,poly(sebacic anhydride)); polyether (e.g., polyethylene glycol);polyurethane; polymethacrylate; polyacrylate; and polycyanoacrylate. Insome embodiments, the polymer may be modified with polyethylene glycol(PEG), with a carbohydrate, and/or with an acyclic polyacetal derivedfrom a polysaccharide. See, e.g., Papisov, 2001, ACS Symposium Series,786:301, incorporated by reference herein.

The compounds of the present invention can be formulated as particles.In one embodiment the particles are or include microparticles. In analternative embodiment the particles are or include nanoparticles.

In an additional alternative embodiment, common techniques for preparingparticles include, but are not limited to, solvent evaporation, solventremoval, spray drying, phase inversion, coacervation, and lowtemperature casting. Suitable methods of particle formulation arebriefly described below. Pharmaceutically acceptable excipients,including pH modifying agents, disintegrants, preservatives, andantioxidants, can optionally be incorporated into the particles duringparticle formation.

In one embodiment, the particles are derived through a solventevaporation method. In this method, a compound described herein (orpolymer matrix and one or more compounds described herein) is dissolvedin a volatile organic solvent, such as methylene chloride. The organicsolution containing a compound described herein is then suspended in anaqueous solution that contains a surface active agent such as poly(vinylalcohol). The resulting emulsion is stirred until most of the organicsolvent evaporated, leaving solid nanoparticles or microparticles. Theresulting nanoparticles or microparticles are washed with water anddried overnight in a lyophilizer. Nanoparticles with different sizes andmorphologies can be obtained by this method.

Pharmaceutical compositions which contain labile polymers, such ascertain polyanhydrides, may degrade during the fabrication process dueto the presence of water. For these polymers, methods which areperformed in completely or substantially anhydrous organic solvents canbe used to make the particles.

Solvent removal can also be used to prepare particles of a compound thatis hydrolytically unstable. In this method, the compound (or polymermatrix and one or more compounds) is dispersed or dissolved in avolatile organic solvent such as methylene chloride. This mixture isthen suspended by stirring in an organic oil (such as silicon oil) toform an emulsion. Solid particles form from the emulsion, which cansubsequently be isolated from the supernatant. The external morphologyof spheres produced with this technique is highly dependent on theidentity of the drug.

In one embodiment an active compound as described herein is administeredto a patient in need thereof as particles formed by solvent removal. Inanother embodiment the present invention provides particles formed bysolvent removal comprising a compound of the present invention and oneor more pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by solvent removal comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by solvent removal comprisea compound of the present invention, an additional therapeutic agent,and one or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by solvent removal canbe formulated into a tablet and then coated to form a coated tablet. Inan alternative embodiment the particles formed by solvent removal areformulated into a tablet but the tablet is uncoated.

In one embodiment, the particles are derived by spray drying. In thismethod, a compound (or polymer matrix and one or more compounds) isdissolved in an organic solvent such as methylene chloride. The solutionis pumped through a micronizing nozzle driven by a flow of compressedgas, and the resulting aerosol is suspended in a heated cyclone of air,allowing the solvent to evaporate from the micro droplets, formingparticles. Microparticles and nanoparticles can be obtained using thismethod.

In one embodiment an active compound as described herein is administeredto a patient in need thereof as a spray dried dispersion (SDD). Inanother embodiment the present invention provides a spray drieddispersion (SDD) comprising a compound of the present invention and oneor more pharmaceutically acceptable excipients as defined herein. Inanother embodiment the SDD comprises a compound of the present inventionand an additional therapeutic agent. In a further embodiment the SDDcomprises a compound of the present invention, an additional therapeuticagent, and one or more pharmaceutically acceptable excipients. Inanother embodiment any of the described spray dried dispersions can becoated to form a coated tablet. In an alternative embodiment the spraydried dispersion is formulated into a tablet but is uncoated.

Particles can be formed from the active compound as described hereinusing a phase inversion method. In this method, the compound (or polymermatrix and one or more active compounds) is dissolved in a suitablesolvent, and the solution is poured into a strong non-solvent for thecompound to spontaneously produce, under favorable conditions,microparticles or nanoparticles. The method can be used to producenanoparticles in a wide range of sizes, including, for example, fromnanoparticles to microparticles, typically possessing a narrow particlesize distribution.

In one embodiment, an active compound as described herein isadministered to a patient in need thereof as particles formed by phaseinversion. In another embodiment the present invention providesparticles formed by phase inversion comprising a compound of the presentinvention and one or more pharmaceutically acceptable excipients asdefined herein. In another embodiment the particles formed by phaseinversion comprise a compound of the present invention and an additionaltherapeutic agent. In a further embodiment the particles formed by phaseinversion comprise a compound of the present invention, an additionaltherapeutic agent, and one or more pharmaceutically acceptableexcipients. In another embodiment any of the described particles formedby phase inversion can be formulated into a tablet and then coated toform a coated tablet. In an alternative embodiment the particles formedby phase inversion are formulated into a tablet but the tablet isuncoated.

Techniques for particle formation using coacervation are known in theart, for example, as described in GB-B-929 406; GB-B-929 40 1; and U.S.Pat. Nos. 3,266,987, 4,794,000, and 4,460,563. Coacervation involves theseparation of a compound (or polymer matrix and one or more compounds)solution into two immiscible liquid phases. One phase is a densecoacervate phase, which contains a high concentration of the compound,while the second phase contains a low concentration of the compound.Within the dense coacervate phase, the compound forms nanoscale ormicroscale droplets, which harden into particles. Coacervation may beinduced by a temperature change, addition of a non-solvent or additionof a micro-salt (simple coacervation), or by the addition of anotherpolymer thereby forming an interpolymer complex (complex coacervation).

In one embodiment an active compound as described herein is administeredto a patient in need thereof as particles formed by coacervation. Inanother embodiment the present invention provides particles formed bycoacervation comprising a compound of the present invention and one ormore pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by coacervation comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by coacervation comprise acompound of the present invention, an additional therapeutic agent, andone or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by coacervation can beformulated into a tablet and then coated to form a coated tablet. In analternative embodiment the particles formed by coacervation areformulated into a tablet but the tablet is uncoated.

Methods for very low temperature casting of controlled releasemicrospheres are described in U.S. Pat. No. 5,019,400 to Gombotz et al.In this method, the compound is dissolved in a solvent. The mixture isthen atomized into a vessel containing a liquid non-solvent at atemperature below the freezing point of the drug solution which freezesthe compound droplets. As the droplets and non-solvent for the compoundare warmed, the solvent in the droplets thaws and is extracted into thenon-solvent, hardening the microspheres.

In one embodiment, a compound of the present invention is administeredto a patient in need thereof as particles formed by low temperaturecasting. In another embodiment the present invention provides particlesformed by low temperature casting comprising a compound of the presentinvention and one or more pharmaceutically acceptable excipients asdefined herein. In another embodiment the particles formed by lowtemperature casting comprise a compound of the present invention and anadditional therapeutic agent. In a further embodiment the particlesformed by low temperature casting comprise a compound of the presentinvention, an additional therapeutic agent, and one or morepharmaceutically acceptable excipients. In another embodiment any of thedescribed particles formed by low temperature casting can be formulatedinto a tablet and then coated to form a coated tablet. In an alternativeembodiment the particles formed by low temperature casting areformulated into a tablet but the tablet is uncoated.

In one aspect of the present invention, an effective amount of an activecompound as described herein is incorporated into a nanoparticle, e.g.for convenience of delivery and/or extended release delivery. The use ofmaterials in nanoscale provides one the ability to modify fundamentalphysical properties such as solubility, diffusivity, blood circulationhalf-life, drug release characteristics, and/or immunogenicity. A numberof nanoparticle-based therapeutic and diagnostic agents have beendeveloped for the treatment of cancer, diabetes, pain, asthma, allergy,and infections. These nanoscale agents may provide more effective and/ormore convenient routes of administration, lower therapeutic toxicity,extend the product life cycle, and ultimately reduce health-care costs.As therapeutic delivery systems, nanoparticles can allow targeteddelivery and controlled release.

In addition, nanoparticle-based compound delivery can be used to releasecompounds at a sustained rate and thus lower the frequency ofadministration, deliver drugs in a targeted manner to minimize systemicside effects, or to deliver two or more drugs simultaneously forcombination therapy to generate a synergistic effect and suppress drugresistance. A number of nanotechnology-based therapeutic products havebeen approved for clinical use. Among these products, liposomal drugsand polymer-based conjugates account for a large proportion of theproducts. See, Zhang, L., et al., Nanoparticles in Medicine: TherapeuticApplications and Developments, Clin. Pharm. and Ther., 83(5):761-769,2008.

Methods for producing nanoparticles are known in the art. For example,see Muller, R. H., et al., Solid lipid nanoparticles (SLN) forcontrolled drug delivery—a review of the state of the art, Eur. H.Pharm. Biopharm., 50:161-177, 2000; U.S. Pat. No. 8,691,750 to Consienet al.; WO 2012/145801 to Kanwar. U.S. Pat. No. 8,580,311 to Armes, S.et al.; Petros, R. A. and DeSimone, J. M., Strategies in the design ofnanoparticles for therapeutic applications, Nature Reviews/DrugDiscovery, vol. 9:615-627, 2010; U.S. Pat. No. 8,465,775; U.S. Pat. No.8,444,899; U.S. Pat. No. 8,420,124; U.S. Pat. No. 8,263,129; U.S. Pat.Nos. 8,158,728; 8,268,446; Pellegrino et al., 2005, Small, 1:48; Murrayet al., 2000, Ann. Rev. Mat. Sci., 30:545; and Trindade et al., 2001,Chem. Mat., 13:3843; all incorporated herein by reference. Additionalmethods have been described in the literature (see, e.g., Doubrow, Ed.,“Microcapsules and Nanoparticles in Medicine and Pharmacy,” CRC Press,Boca Raton, 1992; Mathiowitz et al., 1987, J. Control. Release, 5:13;Mathiowitz et al., 1987, Reactive Polymers, 6:275; and Mathiowitz etal., 1988, J. Appl. Polymer Sci., 35:755; U.S. Pat. Nos. 5,578,325 and6,007,845; P. Paolicelli et al., “Surface-modified PLGA-basedNanoparticles that can Efficiently Associate and Deliver Virus-likeParticles” Nanomedicine. 5(6):843-853 (2010)), U.S. Pat. No. 5,543,158to Gref et al., or WO publication WO2009/051837 by Von Andrian et al.Zauner et al., 1998, Adv. Drug Del. Rev., 30:97; and Kabanov et al.,1995, Bioconjugate Chem., 6:7; (PEI; Boussif et al., 1995, Proc. Natl.Acad. Sci., USA, 1995, 92:7297), and poly(amidoamine) dendrimers(Kukowska-Latallo et al., 1996, Proc. Natl. Acad. Sci., USA, 93:4897;Tang et al., 1996, Bioconjugate Chem., 7:703; and Haensler et al., 1993,Bioconjugate Chem., 4:372; Putnam et al., 1999, Macromolecules, 32:3658;Barrera et al., 1993, J. Am. Chem. Soc., 115:11010; Kwon et al., 1989,Macromolecules, 22:3250; Lim et al., 1999, J. Am. Chem. Soc., 121:5633;and Zhou et al., 1990, Macromolecules, 23:3399). Examples of thesepolyesters include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J.Am. Chem. Soc., 115:11010), poly(serine ester) (Zhou et al., 1990,Macromolecules, 23:3399), poly(4-hydroxy-L-proline ester) (Putnam etal., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem.Soc., 121:5633), and poly(4-hydroxy-L-proline ester) (Putnam et al.,1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc.,121:5633; U.S. Pat. No. 6,123,727; U.S. Pat. No. 5,804,178; U.S. Pat.No. 5,770,417; U.S. Pat. No. 5,736,372; U.S. Pat. No. 5,716,404; U.S.Pat. No. 6,095,148; U.S. Pat. No. 5,837,752; U.S. Pat. No. 5,902,599;U.S. Pat. No. 5,696,175; U.S. Pat. No. 5,514,378; U.S. Pat. No.5,512,600; U.S. Pat. No. 5,399,665; U.S. Pat. No. 5,019,379; U.S. Pat.No. 5,010,167; U.S. Pat. No. 4,806,621; U.S. Pat. No. 4,638,045; andU.S. Pat. No. 4,946,929; Wang et al., 2001, J. Am. Chem. Soc., 123:9480;Lim et al., 2001, J. Am. Chem. Soc., 123:2460; Langer, 2000, Acc. Chem.Res., 33:94; Langer, 1999, J. Control. Release, 62:7; and Uhrich et al.,1999, Chem. Rev., 99:3181; Concise Encyclopedia of Polymer Science andPolymeric Amines and Ammonium Salts, Ed. by Goethals, Pergamon Press,1980; Principles of Polymerization by Odian, John Wiley & Sons, FourthEdition, 2004; Contemporary Polymer Chemistry by Allcock et al.,Prentice-Hall, 1981; Deming et al., 1997, Nature, 390:386; and in U.S.Pat. Nos. 6,506,577, 6,632,922, 6,686,446, and 6,818,732; C. Astete etal., “Synthesis and characterization of PLGA nanoparticles” J. Biomater.Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 (2006); K. Avgoustakis“Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles:Preparation, Properties and Possible Applications in Drug Delivery”Current Drug Delivery 1:321-333 (2004); C. Reis et al.,“Nanoencapsulation I. Methods for preparation of drug-loaded polymericnanoparticles” Nanomedicine 2:8-21 (2006); P. Paolicelli et al.,“Surface-modified PLGA-based Nanoparticles that can EfficientlyAssociate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853(2010); U.S. Pat. No. 6,632,671 to Unger Oct. 14, 2003, all incorporatedherein by reference.

In one embodiment, the polymeric particle is between about 0.1 nm toabout 10000 nm, between about 1 nm to about 1000 nm, between about 10 nmand 1000 nm, between about 1 and 100 nm, between about 1 and 10 nm,between about 1 and 50 nm, between about 100 nm and 800 nm, betweenabout 400 nm and 600 nm, or about 500 nm. In one embodiment, themicro-particles are no more than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm,10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm. Insome embodiments, a compound described herein may be covalently coupledto a polymer used in the nanoparticle, for example a polystyreneparticle, PLGA particle, PLA particle, or other nanoparticle.

The pharmaceutical compositions can be formulated for oraladministration. These compositions can contain any amount of activecompound that achieves the desired result, for example between 0.1 and99 weight % (wt. %) of the compound and usually at least about 5 wt. %of the compound. Some embodiments contain at least about 10%, 15%, 20%,25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % ofthe compound.

Pharmaceutical compositions suitable for rectal administration aretypically presented as unit dose suppositories. These may be prepared byadmixing the active compound with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Pharmaceutical compositions suitable for topical application to the skinpreferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Carriers which may be used include petroleumjelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers,and combinations of two or more thereof.

Pharmaceutical compositions suitable for transdermal administration maybe presented as discrete patches adapted to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time.Pharmaceutical compositions suitable for transdermal administration mayalso be delivered by iontophoresis (see, for example, PharmaceuticalResearch 3 (6):318 (1986)) and typically take the form of an optionallybuffered aqueous solution of the active compound. In one embodiment,microneedle patches or devices are provided for delivery of drugs acrossor into biological tissue, particularly the skin. The microneedlepatches or devices permit drug delivery at clinically relevant ratesacross or into skin or other tissue barriers, with minimal or no damage,pain, or irritation to the tissue.

Pharmaceutical compositions suitable for administration to the lungs canbe delivered by a wide range of passive breath driven and active powerdriven single/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

Additional non-limiting examples of inhalation drug delivery devices andmethods include, for example, U.S. Pat. No. 7,383,837 titled “Inhalationdevice” (SmithKline Beecham Corporation); WO/2006/033584 titled “Powderinhaler” (Glaxo SmithKline Pharmaceuticals SA); WO/2005/044186 titled“Inhalable pharmaceutical formulations employing desiccating agents andmethods of administering the same” (Glaxo Group Ltd and SmithKlineBeecham Corporation); U.S. Pat. No. 9,095,670 titled “Inhalation deviceand method of dispensing medicament”, U.S. Pat. No. 8,205,611 titled“Dry powder inhaler” (Astrazeneca AB); WO/2013/038170 titled “Inhaler”(Astrazeneca AB and Astrazeneca UK Ltd.); US/2014/0352690 titled“Inhalation Device with Feedback System”, U.S. Pat. No. 8,910,625 andUS/2015/0165137 titled “Inhalation Device for Use in Aerosol Therapy”(Vectura GmbH); U.S. Pat. No. 6,948,496 titled “Inhalers”,US/2005/0152849 titled “Powders comprising anti-adherent materials foruse in dry powder inhalers”, U.S. Pat. No. 6,582,678, U.S. Pat. No.8,137,657, US/2003/0202944, and US/2010/0330188 titled “Carrierparticles for use in dry powder inhalers”, U.S. Pat. No. 6,221,338titled “Method of producing particles for use in dry powder inhalers”,U.S. Pat. No. 6,989,155 titled “Powders”, US/2007/0043030 titled“Pharmaceutical compositions for treating premature ejaculation bypulmonary inhalation”, U.S. Pat. No. 7,845,349 titled “Inhaler”,US/2012/0114709 and U.S. Pat. No. 8,101,160 titled “Formulations for Usein Inhaler Devices”, US/2013/0287854 titled “Compositions and Uses”,US/2014/0037737 and U.S. Pat. No. 8,580,306 titled “Particles for Use ina Pharmaceutical Composition”, US/2015/0174343 titled “Mixing Channelfor an Inhalation Device”, U.S. Pat. No. 7,744,855 and US/2010/0285142titled “Method of making particles for use in a pharmaceuticalcomposition”, U.S. Pat. No. 7,541,022, US/2009/0269412, andUS/2015/0050350 titled “Pharmaceutical formulations for dry powderinhalers” (Vectura Limited).

Many methods and devices for drug delivery to the eye are known in theart. Non-limiting examples are described in the following patents andpatent applications (fully incorporated herein by reference). Examplesare U.S. Pat. No. 8,192,408 titled “Ocular trocar assembly” (Psivida Us,Inc.); U.S. Pat. No. 7,585,517 titled “Transcleral delivery” (Macusight,Inc.); U.S. Pat. No. 5,710,182 and U.S. Pat. No. 5,795,913 titled“Ophthalmic composition” (Santen O Y); U.S. Pat. No. 8,663,639 titled“Formulations for treating ocular diseases and conditions”, U.S. Pat.No. 8,486,960 titled “Formulations and methods for vascularpermeability-related diseases or conditions”, U.S. Pat. No. 8,367,097and U.S. Pat. No. 8,927,005 titled “Liquid formulations for treatment ofdiseases or conditions”, U.S. Pat. No. 7,455,855 titled “Deliveringsubstance and drug delivery system using the same” (SantenPharmaceutical Co., Ltd.); WO/2011/050365 titled “ConformableTherapeutic Shield For Vision and Pain” and WO/2009/145842 titled“Therapeutic Device for Pain Management and Vision” (Forsight Labs,LLC); U.S. Pat. No. 9,066,779 and U.S. Pat. No. 8,623,395 titled“Implantable therapeutic device”, WO/2014/160884 titled “OphthalmicImplant for Delivering Therapeutic Substances”, U.S. Pat. No. 8,399,006,U.S. Pat. No. 8,277,830, U.S. Pat. No. 8,795,712, U.S. Pat. No.8,808,727, U.S. Pat. No. 8,298,578, and WO/2010/088548 titled “Posteriorsegment drug delivery”, WO/2014/152959 and US20140276482 titled “Systemsfor Sustained Intraocular Delivery of Low Solubility Compounds from aPort Delivery System Implant”, U.S. Pat. No. 8,905,963 and U.S. Pat. No.9,033,911 titled “Injector apparatus and method for drug delivery”,WO/2015/057554 titled “Formulations and Methods for Increasing orReducing Mucus”, U.S. Pat. No. 8,715,712 and U.S. Pat. No. 8,939,948titled “Ocular insert apparatus and methods”, WO/2013/116061 titled“Insertion and Removal Methods and Apparatus for Therapeutic Devices”,WO/2014/066775 titled “Ophthalmic System for Sustained Release of Drugto the Eye”, WO/2015/085234 and WO/2012/019176 titled “ImplantableTherapeutic Device”, WO/2012/065006 titled “Methods and Apparatus todetermine Porous Structures for Drug Delivery”, WO/2010/141729 titled“Anterior Segment Drug Delivery”, WO/2011/050327 titled “CornealDenervation for Treatment of Ocular Pain”, WO/2013/022801 titled “SmallMolecule Delivery with Implantable Therapeutic Device”, WO/2012/019047titled “Subconjunctival Implant for Posterior Segment Drug Delivery”,WO/2012/068549 titled “Therapeutic Agent Formulations for ImplantedDevices”, WO/2012/019139 titled “Combined Delivery Methods andApparatus”, WO/2013/040426 titled “Ocular Insert Apparatus and Methods”,WO/2012/019136 titled “Injector Apparatus and Method for Drug Delivery”,WO/2013/040247 titled “Fluid Exchange Apparatus and Methods” (ForSightVision4, Inc.).

Additional non-limiting examples of how to deliver the active compoundsare provided in WO/2015/085251 titled “Intracameral Implant forTreatment of an Ocular Condition” (Envisia Therapeutics, Inc.);WO/2011/008737 titled “Engineered Aerosol Particles, and AssociatedMethods”, WO/2013/082111 titled “Geometrically Engineered Particles andMethods for Modulating Macrophage or Immune Responses”, WO/2009/132265titled “Degradable compounds and methods of use thereof, particularlywith particle replication in non-wetting templates”, WO/2010/099321titled “Interventional drug delivery system and associated methods”,WO/2008/100304 titled “Polymer particle composite having high fidelityorder, size, and shape particles”, WO/2007/024323 titled “Nanoparticlefabrication methods, systems, and materials” (Liquidia Technologies,Inc. and the University of North Carolina at Chapel Hill);WO/2010/009087 titled “Iontophoretic Delivery of a Controlled-ReleaseFormulation in the Eye”, (Liquidia Technologies, Inc. and EyegatePharmaceuticals, Inc.) and WO/2009/132206 titled “Compositions andMethods for Intracellular Delivery and Release of Cargo”, WO/2007/133808titled “Nano-particles for cosmetic applications”, WO/2007/056561 titled“Medical device, materials, and methods”, WO/2010/065748 titled “Methodfor producing patterned materials”, WO/2007/081876 titled“Nanostructured surfaces for biomedical/biomaterial applications andprocesses thereof” (Liquidia Technologies, Inc.).

Additional non-limiting examples of methods and devices for drugdelivery to the eye include, for example, WO2011/106702 and U.S. Pat.No. 8,889,193 titled “Sustained delivery of therapeutic agents to an eyecompartment”, WO2013/138343 and U.S. Pat. No. 8,962,577 titled“Controlled release formulations for the delivery of HIF-1 inhibitors”,WO/2013/138346 and US2013/0272994 titled “Non-Linear MultiblockCopolymer-Drug Conjugates for the Delivery of Active Agents”,WO2005/072710 and U.S. Pat. No. 8,957,034 titled “Drug and Gene CarrierParticles that Rapidly Move Through Mucus Barriers”, WO2008/030557,US2010/0215580, US2013/0164343 titled “Compositions and Methods forEnhancing Transport Through Mucous”, WO2012/061703, US2012/0121718, andUS2013/0236556 titled “Compositions and Methods Relating to ReducedMucoadhesion”, WO2012/039979 and US2013/0183244 titled “Rapid Diffusionof Large Polymeric Nanoparticles in the Mammalian Brain”, WO2012/109363and US2013/0323313 titled “Mucus Penetrating Gene Carriers”, WO2013/090804 and US2014/0329913 titled “Nanoparticles with enhancedmucosal penetration or decreased inflammation”, WO2013/110028 titled“Nanoparticle formulations with enhanced mucosal penetration”,WO2013/166498 and US2015/0086484 titled “Lipid-based drug carriers forrapid penetration through mucus linings” (The Johns Hopkins University);WO2013/166385 titled “Pharmaceutical Nanoparticles Showing ImprovedMucosal Transport”, US2013/0323179 titled “Nanocrystals, Compositions,And Methods that Aid Particle Transport in Mucus” (The Johns HopkinsUniversity and Kala Pharmaceuticals, Inc.); WO/2015/066444 titled“Compositions and methods for ophthalmic and/or other applications”,WO/2014/020210 and WO/2013/166408 titled “Pharmaceutical nanoparticlesshowing improved mucosal transport” (Kala Pharmaceuticals, Inc.); U.S.Pat. No. 9,022,970 titled “Ophthalmic injection device including dosagecontrol device”, WO/2011/153349 titled “Ophthalmic compositionscomprising pbo-peo-pbo block copolymers”, WO/2011/140203 titled“Stabilized ophthalmic galactomannan formulations”, WO/2011/068955titled “Ophthalmic emulsion”, WO/2011/037908 titled “Injectable aqueousophthalmic composition and method of use therefor”, US2007/0149593titled “Pharmaceutical Formulation for Delivery of Receptor TyrosineKinase Inhibiting (RTKi) Compounds to the Eye”, U.S. Pat. No. 8,632,809titled “Water insoluble polymer matrix for drug delivery” (Alcon, Inc.).

Additional non-limiting examples of drug delivery devices and methodsinclude, for example, US20090203709 titled “Pharmaceutical Dosage FormFor Oral Administration Of Tyrosine Kinase Inhibitor” (AbbottLaboratories); US20050009910 titled “Delivery of an active drug to theposterior part of the eye via subconjunctival or periocular delivery ofa prodrug”, US 20130071349 titled “Biodegradable polymers for loweringintraocular pressure”, U.S. Pat. No. 8,481,069 titled “Tyrosine kinasemicrospheres”, U.S. Pat. No. 8,465,778 titled “Method of making tyrosinekinase microspheres”, U.S. Pat. No. 8,409,607 titled “Sustained releaseintraocular implants containing tyrosine kinase inhibitors and relatedmethods”, U.S. Pat. No. 8,512,738 and US 2014/0031408 titled“Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986titled “Microsphere Drug Delivery System for Sustained IntraocularRelease”, U.S. Pat. No. 8,911,768 titled “Methods For TreatingRetinopathy With Extended Therapeutic Effect” (Allergan, Inc.); U.S.Pat. No. 6,495,164 titled “Preparation of injectable suspensions havingimproved inj ectability” (Alkermes Controlled Therapeutics, Inc.); WO2014/047439 titled “Biodegradable Microcapsules Containing FillingMaterial” (Akina, Inc.); WO 2010/132664 titled “Compositions And MethodsFor Drug Delivery” (Baxter International Inc. Baxter Healthcare SA);US20120052041 titled “Polymeric nanoparticles with enhanced drugloadingand methods of use thereof” (The Brigham and Women's Hospital, Inc.);US20140178475, US20140248358, and US20140249158 titled “TherapeuticNanoparticles Comprising a Therapeutic Agent and Methods of Making andUsing Same” (BIND Therapeutics, Inc.); U.S. Pat. No. 5,869,103 titled“Polymer microparticles for drug delivery” (Danbiosyst UK Ltd.); U.S.Pat. No. 8,628,801 titled “Pegylated Nanoparticles” (Universidad deNavarra); US2014/0107025 titled “Ocular drug delivery system” (JadeTherapeutics, LLC); U.S. Pat. No. 6,287,588 titled “Agent deliveringsystem comprised of microparticle and biodegradable gel with an improvedreleasing profile and methods of use thereof”, U.S. Pat. No. 6,589,549titled “Bioactive agent delivering system comprised of microparticleswithin a biodegradable to improve release profiles” (Macromed, Inc.);U.S. Pat. No. 6,007,845 and U.S. Pat. No. 5,578,325 titled“Nanoparticles and microparticles of non-linear hydrophilichydrophobicmultiblock copolymers” (Massachusetts Institute of Technology);US20040234611, US20080305172, US20120269894, and US20130122064 titled“Ophthalmic depot formulations for periocular or subconjunctivaladministration (Novartis Ag); U.S. Pat. No. 6,413,539 titled “Blockpolymer” (Poly-Med, Inc.); US 20070071756 titled “Delivery of an agentto ameliorate inflammation” (Peyman); US 20080166411 titled “InjectableDepot Formulations And Methods For Providing Sustained Release Of PoorlySoluble Drugs Comprising Nanoparticles” (Pfizer, Inc.); U.S. Pat. No.6,706,289 titled “Methods and compositions for enhanced delivery ofbioactive molecules” (PR Pharmaceuticals, Inc.); and U.S. Pat. No.8,663,674 titled “Microparticle containing matrices for drug delivery”(Surmodics).

IV. Uses of Active Compounds for Treatment of Selected Disorders

In one aspect, an active compound or its salt or composition, asdescribed herein is used to treat a medical disorder which is aninflammatory or immune condition, a disorder mediated by the complementcascade (including a dysfunctional cascade) including a complementD-related disorder, a disorder or abnormality of a cell that adverselyaffects the ability of the cell to engage in or respond to normalcomplement activity, or an undesired complement-mediated response to amedical treatment, such as surgery or other medical procedure or apharmaceutical or biopharmaceutical drug administration, a bloodtransfusion, or other allogenic tissue or fluid administration.

Section A Disorders

In one embodiment, the invention is the use of a compound of Formula I,or a pharmaceutically acceptable salt or composition thereof, as well asthe compounds of Table 1, Table 2, Table 3 or an embodiment of theactive compound as described in the Figures for the treatment of adisorder as described in this Section A herein.

In one embodiment, the disorder is selected from fatty liver andconditions stemming from fatty liver, such as nonalcoholicsteatohepatitis (NASH), liver inflammation, cirrhosis and liver failure.In one embodiment of the present invention, a method is provided fortreating fatty liver disease in a host by administering an effectiveamount of a compound of Formula I, Table 1, Table 2, Table 3 or anembodiment of the active compound as described in the Figures or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In one embodiment of the presentinvention, a method is provided for treating nonalcoholicsteatohepatitis (NASH) in a host by administering an effective amount ofa compound of Formula I, Table 1, Table 2, Table 3 or an embodiment ofthe active compound as described in the Figures, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier.

In another embodiment, the active compound is used to modulate an immuneresponse prior to or during surgery or other medical procedure. Onenon-limiting example is use in connection with acute or chronic graftversus host disease, which is a common complication as a result ofallogeneic tissue transplant, and can also occur as a result of a bloodtransfusion.

In one embodiment, the present invention provides a method of treatingor preventing dermatomyositis by administering to a host in need thereofan effective amount of a composition comprising a compound of thecurrent invention. In one embodiment, the present invention provides amethod of treating or preventing amyotrophic lateral sclerosis byadministering to a host in need thereof an effective amount of acomposition comprising a compound of the current invention.

In another embodiment, a method is provided for the treatment orprevention of cytokine or inflammatory reactions in response to theadministration of biotherapeutics (e.g. CAR T-cell therapy or monoclonalantibody therapy) in a host by administering an effective amount of acompound of Formula I, Table 1, Table 2, Table 3 or an embodiment of theactive compound as described in the Figures, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier, or a pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. Various types of cytokine orinflammatory reactions may occur in response to biotherapeutics. In oneembodiment, the cytokine or inflammatory reaction is cytokine releasesyndrome. In one embodiment, the cytokine or inflammatory reaction istumor lysis syndrome (which also leads to cytokine release). Symptoms ofcytokine release syndrome range from fever, headache, and skin rashes tobronchospasm, hypotension and even cardiac arrest. Severe cytokinerelease syndrome is described as cytokine storm, and can be fatal. Fatalcytokine storms have been observed in response to infusion with severalmonoclonal antibody therapeutics. See, Abramowicz D, et al. “Release oftumor necrosis factor, interleukin-2, and gamma-interferon in serumafter injection of OKT3 monoclonal antibody in kidney transplantrecipients” Transplantation (1989) 47(4):606-8; Chatenoud L, et al. “Invivo cell activation following OKT3 administration. Systemic cytokinerelease and modulation by corticosteroids” Transplantation (1990)49(4):697-702; and Lim L C, Koh L P, and Tan P. “Fatal cytokine releasesyndrome with chimeric anti-CD20 monoclonal antibody rituximab in a71-year-old patient with chronic lymphocytic leukemia” J. Clin Oncol.(1999) 17(6):1962-3.

Also contemplated herein, is the use of a compound of Formula I, Table1, Table 2, Table 3 or an embodiment of the active compound as describedin the Figures, or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutically acceptable carrier to mediate anadverse immune response in patients receiving bi-specific T-cellengagers (BiTE). A bi-specific T-cell engager directs T-cells to targetand bind with a specific antigen on the surface of a cancer cell. Forexample, Blinatumomab (Amgen), a BiTE has recently been approved as asecond line therapy in Philadelphia chromosome-negative relapsed orrefractory acute lymphoblastic leukemia. Blinatumomab is given bycontinuous intravenous infusion in 4-week cycles. The use of BiTE agentshas been associated with adverse immune responses, including cytokinerelease syndrome. The most significantly elevated cytokines in the CRSassociated with ACT include IL-10, IL-6, and IFN-γ (Klinger et al.,Immunopharmacologic response of patients with B-lineage acutelymphoblastic leukemia to continuous infusion of T cell-engagingCD19/CD3-bispecific BiTE antibody blinatumomab. Blood (2012)119:6226-6233).

In another embodiment, the disorder is episcleritis, idiopathicepiscleritis, anterior episcleritis, or posterior episcleritis. In oneembodiment, the disorder is idiopathic anterior uveitis, HLA-B27 relateduveitis, herpetic keratouveitis, Posner Schlossman syndrome, Fuch'sheterochromic iridocyclitis, or cytomegalovirus anterior uveitis.

In yet another embodiment, the disorder is selected from:

-   (i) vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease;-   (ii) retinal vasculitis, Eales disease, tuberculosis, syphilis, or    toxoplasmosis;-   (iii) neuroretinitis, viral retinitis, or acute retinal necrosis;-   (iv) varicella zoster virus, herpes simplex virus, cytomegalovirus,    Epstein-Barr virus, lichen planus, or Dengue-associated disease    (e.g., hemorraghic Dengue Fever);-   (v) Masquerade syndrome, contact dermatitis, trauma induced    inflammation, UVB induced inflammation, eczema, granuloma annulare,    or acne.

In an additional embodiment, the disorder is selected from:

-   (i) acute myocardial infarction, aneurysm, cardiopulmonary bypass,    dilated cardiomyopathy, complement activation during cardiopulmonary    bypass operations, coronary artery disease, restenosis following    stent placement, or percutaneous transluminal coronary angioplasty    (PTCA);-   (ii) antibody-mediated transplant rejection, anaphylactic shock,    anaphylaxis, allogenic transplant, humoral and vascular transplant    rejection, graft dysfunction, graft-versus-host disease, Graves'    disease, adverse drug reactions, or chronic graft vasculopathy;-   (iii) allergic bronchopulmonary aspergillosis, allergic neuritis,    drug allergy, radiation-induced lung injury, eosinophilic pneumonia,    radiographic contrast media allergy, bronchiolitis obliterans, or    interstitial pneumonia;-   (iv) amyotrophic lateral sclerosis, parkinsonism-dementia complex,    sporadic frontotemporal dementia, frontotemporal dementia with    Parkinsonism linked to chromosome 17, frontotemporal lobar    degeneration, tangle only dementia, cerebral amyloid angiopathy,    cerebrovascular disorder, certain forms of frontotemporal dementia,    chronic traumatic encephalopathy (CTE), PD with dementia (PDD),    argyrophilic grain dementia, dementia pugilistica, dementia with    Lewy Bodies (DLB), or multi-infarct dementia;-   (v) Creutzfeldt-Jakob disease, Huntington's disease, multifocal    motor neuropathy (MMN), prion protein cerebral amyloid angiopathy,    polymyositis, postencephalitic parkinsonism, subacute sclerosing    panencephalitis, non-Guamanian motor neuron disease with    neurofibrillary tangles, neural regeneration, or diffuse    neurofibrillary tangles with calcification.

In one embodiment, the disorder is selected from:

-   (i) atopic dermatitis, dermatitis, dermatomyositis, dermatomyositis    bullous pemphigoid, scleroderma, sclerodermatomyositis, psoriatic    arthritis, pemphigus vulgaris, cutaneous lupus, discoid lupus    erythematosus, chilblain lupus erythematosus, or lupus    erythematosus-lichen planus overlap syndrome;-   (ii) cryoglobulinemic vasculitis, mesenteric/enteric vascular    disorder, peripheral vascular disorder, antineutrophil cytoplasm    antibody (ANCA)-associated vasculitis (AAV), IL-2 induced vascular    leakage syndrome, or immune complex vasculitis;-   (iii) angioedema, low platelets (HELLP) syndrome, sickle cell    disease, platelet refractoriness, red cell casts, or typical or    infectious hemolytic uremic syndrome (tHUS);-   (iv) hematuria, hemodialysis, hemolysis, hemorrhagic shock,    immunothrombocytopenic purpura (ITP), thrombotic thrombocytopenic    purpura (TTP), idiopathic thrombocytopenic purpura (ITP),    drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA),    azotemia, blood vessel and/or lymph vessel inflammation, rotational    atherectomy, or delayed hemolytic transfusion reaction;-   (v) British type amyloid angiopathy, Buerger's disease, bullous    pemphigoid, Clq nephropathy, cancer, or catastrophic    antiphospholipid syndrome.

In another embodiment, the disorder is selected from:

-   (i) wet AMD, dry AMD, chorioretinal degeneration, choroidal    neovascularization (CNV), choroiditis, loss of RPE function, loss of    vision (including loss of visual acuity or visual field), loss of    vision from AMD, retinal damage in response to light exposure,    retinal degeneration, retinal detachment, retinal dysfunction,    retinal neovascularization (RNV), retinopathy of prematurity, or RPE    degeneration;-   (ii) pseudophakic bullous keratopathy, symptomatic macular    degeneration related disorder, optic nerve degeneration,    photoreceptor degeneration, cone degeneration, loss of photoreceptor    cells, pars planitis, scleritis, proliferative vitreoretinopathy, or    formation of ocular drusen;-   (iii) chronic urticaria, Churg-Strauss syndrome, cold agglutinin    disease (CAD), corticobasal degeneration (CBD), cryoglobulinemia,    cyclitis, damage of the Bruch's membrane, Degos disease, diabetic    angiopathy, elevated liver enzymes, endotoxemia, epidermolysis    bullosa, or epidermolysis bullosa acquisita;-   (iv) essential mixed cryoglobulinemia, excessive blood urea    nitrogen-BUN, focal segmental glomerulosclerosis,    Gerstmann-Straussler-Scheinker disease, giant cell arteritis, gout,    Hallervorden-Spatz disease, Hashimoto's thyroiditis,    Henoch-Schonlein purpura nephritis, or abnormal urinary sediments;-   (v) hepatitis, hepatitis A, hepatitis B, hepatitis C or human    immunodeficiency virus (HIV),-   (vi) a viral infection more generally, for example selected from    Flaviviridae, Retroviruses, Coronaviridae, Poxviridae, Adenoviridae,    Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae,    Togaviridae, Orthomyxoviridae, Rhabdoviridae, or Hepadnaviridae;-   (vii) Neisseria meningitidis, shiga toxin E. coli-related hemolytic    uremic syndrome (STEC-HUS), Streptococcus, or poststreptococcal    glomerulonephritis.

In a further embodiment, the disorder is selected from:

-   (viii) hyperlipidemia, hypertension, hypoalbuminemia, hypobolemic    shock, hypocomplementemic urticarial vasculitis syndrome,    hypophosphastasis, hypovolemic shock, idiopathic pneumonia syndrome,    or idiopathic pulmonary fibrosis;-   (ix) inclusion body myositis, intestinal ischemia, iridocyclitis,    iritis, juvenile chronic arthritis, Kawasaki's disease (arteritis),    or lipiduria;-   (x) membranoproliferative glomerulonephritis (MPGN) I, microscopic    polyangiitis, mixed cryoglobulinemia, molybdenum cofactor deficiency    (MoCD) type A, pancreatitis, panniculitis, Pick's disease,    polyarteritis nodosa (PAN), progressive subcortical gliosis,    proteinuria, reduced glomerular filtration rate (GFR), or    renovascular disorder;-   (xi) multiple organ failure, multiple system atrophy (MSA), myotonic    dystrophy, Niemann-Pick disease type C, chronic demyelinating    diseases, or progressive supranuclear palsy;-   (xii) spinal cord injury, spinal muscular atrophy,    spondyloarthropathies, Reiter's syndrome, spontaneous fetal loss,    recurrent fetal loss, pre-eclampsia, synucleinopathy, Takayasu's    arteritis, post-partum thryoiditis, thyroiditis, Type I    cryoglobulinemia, Type II mixed cryoglobulinemia, Type III mixed    cryoglobulinemia, ulcerative colitis, uremia, urticaria, venous gas    embolus (VGE), or Wegener's granulomatosis;

In one embodiment, a compound described herein is useful for treating orpreventing a disorder selected from autoimmune oophoritis,endometriosis, autoimmune orchitis, Ord's thyroiditis, autoimmuneenteropathy, coeliac disease, Hashimoto's encephalopathy,antiphospholipid syndrome (APLS) (Hughes syndrome), aplastic anemia,autoimmune lymphoproliferative syndrome (Canale-Smith syndrome),autoimmune neutropenia, Evans syndrome, pernicious anemia, pure red cellaplasia, thrombocytopenia, adipose dolorosa (Dercum's disease), adultonset Still's disease, ankylosing spondylitis, CREST syndrome,drug-induced lupus, eosinophilic fasciitis (Shulman's syndrome), Feltysyndrome, IgG4-related disease, mixed connective tissue disease (MCTD),palindromic rheumatism (Hench-Rosenberg syndrome), Parry-Rombergsyndrome, Parsonage-Turner syndrome, relapsing polychondritis(Meyenburg-Altherr-Uehlinger syndrome), retroperitonial fibrosis,rheumatic fever, Schnitzler syndrome, fibromyalgia, neuromyotonia(Isaac's disease), paraneoplastic degeneration, autoimmune inner eardisease, Meniere's disease, interstitial cystitis, autoimmunepancreatitis, zika virus-related disorders, chikungunya virus-relateddisorders, subacute bacterial endocarditis (SBE), IgA nephropathy, IgAvasculitis, polymyalgia rheumatic, rheumatoid vasculitis, alopeciaareata, autoimmune progesterone dermatitis, dermatitis herpetiformis,erythema nodosum, gestational pemphigoid, hidradenitis suppurativa,lichen sclerosus, linear IgA disease (LAD), morphea, myositis,pityriasis lichenoides et varioliformis acuta, vitiligo post-myocardialinfarction syndrome (Dressler's syndrome), post-pericardiotomy syndrome,autoimmune retinopathy, Cogan syndrome, Graves opthalmopathy, ligneousconjunctivitis, Mooren's ulcer, opsoclonus myoclonus syndrome, opticneuritis, retinocochleocerebral vasculopathy (Susac's syndrome),sympathetic opthalmia, Tolosa-Hunt syndrome, interstitial lung disease,antisynthetase syndrome, Addison's disease, autoimmune polyendocrinesyndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II,autoimmune polyendocrine syndrome (APS) type III, disseminated sclerosis(multiple sclerosis, pattern II), rapidly progressing glomerulonephritis(RPGN), juvenile rheumatoid arthritis, enthesitis-related arthritis,reactive arthritis (Reiter's syndrome), autoimmune hepatitis or lupoidhepatitis, primary biliary cirrhosis (PBS), primary sclerosingcholangitis, microscopic colitis, latent lupus (undifferentiatedconnective tissue disease (UCTD)), acute disseminated encephalomyelitis(ADEM), acute motor axonal neuropathy, anti-n-methyl-D-aspartatereceptor encephalitis, Balo concentric sclerosis (Schilders disease),Bickerstaff's encephalitis, chronic inflammatory demyelinatingpolyneuropathy, idiopathic inflammatory demyelinating disease,Lambert-Eaton mysathenic syndrome, Oshtoran syndrome, pediatricautoimmune neuropsychiatric disorder associated with streptococcus(PANDAS), progressive inflammatory neuropathy, restless leg syndrome,stiff person syndrome, Sydenhem syndrome, transverse myelitis, lupusvasculitis, leukocytoclastic vasculitis, Microscopic Polyangiitis,polymyositis, ischemic-reperfusion injury of the eye.

In one embodiment, a method for the treatment of sickle cell in a hostis provided that includes the administration of an effective amount of acompound described herein, or its salt, optionally in a pharmaceuticallyacceptable carrier. In one embodiment, a method for the treatment ofimmunothrombocytopenic purpura (ITP), thrombotic thrombocytopenicpurpura (TTP), or idiopathic thrombocytopenic purpura (ITP) in a host isprovided that includes the administration of an effective amount of acompound described herein, or its salt, optionally in a pharmaceuticallyacceptable carrier. In one embodiment, a method for the treatment ofANCA-vasculitis in a host is provided that includes the administrationof an effective amount of a compound described herein, or its salt,optionally in a pharmaceutically acceptable carrier. In one embodiment,a method for the treatment of IgA nephropathy in a host is provided thatincludes the administration of an effective amount of a compounddescribed herein, or its salt, optionally in a pharmaceuticallyacceptable carrier. In one embodiment, a method for the treatment ofrapidly progressing glomerulonephritis (RPGN), in a host is providedthat includes the administration of an effective amount of a compounddescribed herein, or its salt, optionally in a pharmaceuticallyacceptable carrier. In one embodiment, a method for the treatment oflupus nephritis, in a host is provided that includes the administrationof an effective amount of a compound described herein, or its salt,optionally in a pharmaceutically acceptable carrier. In one embodiment,a method for the treatment of hemorraghic dengue fever, in a host isprovided that includes the administration of an effective amount of acompound described herein, or its salt, optionally in a pharmaceuticallyacceptable carrier.

Section B Disorders

The compound of Table 2 or Table 3 or their pharmaceutically acceptablesalts or pharmaceutical compositions are useful for treating any of thedisorders described herein. In one embodiment, the compound is usefulfor treating or preventing a disorder that is mediated by the complementpathway, and in particular, a pathway that is modulated by complementFactor D. In another embodiment, the compound is effective to treat thenamed disorder, albeit through a different mechanism.

In certain embodiments, the disorder is an inflammatory disorder, animmune disorder, an autoimmune disorder, or complement Factor D relateddisorders in a host. In one embodiment, the disorder is an oculardisorder or an eye disorder.

Examples of eye disorders that may be treated according to thecompositions and methods disclosed herein include amoebic keratitis,fungal keratitis, bacterial keratitis, viral keratitis, onchorcercalkeratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis,corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren'ssyndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases,environmental dry eye diseases, corneal neovascularization diseases,post-corneal transplant rejection prophylaxis and treatment, autoimmuneuveitis, infectious uveitis, anterior uveitis, posterior uveitis(including toxoplasmosis), pan-uveitis, an inflammatory disease of thevitreous or retina, endophthalmitis prophylaxis and treatment, macularedema, macular degeneration, age related macular degeneration,proliferative and non-proliferative diabetic retinopathy, hypertensiveretinopathy, an autoimmune disease of the retina, primary and metastaticintraocular melanoma, other intraocular metastatic tumors, open angleglaucoma, closed angle glaucoma, pigmentary glaucoma and combinationsthereof.

In a further embodiment, the disorder is selected from age-relatedmacular degeneration, glaucoma, diabetic retinopathy, neuromyelitisoptica (NMO), vasculitis, hemodialysis, blistering cutaneous diseases(including bullous pemphigoid, pemphigus, and epidermolysis bullosa),ocular cicatrical pemphigoid, uveitis, adult macular degeneration,diabetic retinopa retinitis pigmentosa, macular edema, Behcet's uveitis,multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediateuveitis, birdshot retino-chorioditis, sympathetic ophthalmia, oculardicatricial pemphigoid, ocular pemphigus, nonartertic ischemic opticneuropathy, postoperative inflammation, and retinal vein occlusion, oruveitis (including Behcet's disease and other sub-types of uveitis).

In some embodiments, complement mediated diseases include ophthalmicdiseases (including early or neovascular age-related maculardegeneration and geographic atrophy), autoimmune diseases (includingarthritis, rheumatoid arthritis), respiratory diseases, cardiovasculardiseases. In other embodiments, the compounds of the invention aresuitable for use in the treatment of diseases and disorders associatedwith fatty acid metabolism, including obesity and other metabolicdisorders.

Complement mediated disorders that may be treated or prevented by thecompounds of Table 2 or Table 3 include, but are not limited to:

-   (i) paroxysmal nocturnal hemoglobinuria (PNH), hereditary    angioedema, capillary leak syndrome, atypical hemolytic uremic    syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic    aneurysm, hemodialysis complications, hemolytic anemia, or    hemodialysis;-   (ii) myasthenia gravis, multiple sclerosis, C3 glomerulonephritis    (C3GNs), MPGN II (dense deposit disease), neurological disorders,    Guillain Barre Syndrome, diseases of the central nervous system and    other neurodegenerative conditions, glomerulonephritis (including    membrane proliferative glomerulonephritis), SLE nephritis,    proliferative nephritis, liver fibrosis, tissue regeneration and    neural regeneration, or Barraquer-Simons Syndrome;-   (iii) inflammatory effects of sepsis, systemic inflammatory response    syndrome (SIRS), disorders of inappropriate or undesirable    complement activation, interleukin-2 induced toxicity during IL-2    therapy, inflammatory disorders, inflammation of autoimmune    diseases, system lupus erythematosus (SLE), Crohn's disease,    rheumatoid arthritis, inflammatory bowel disease, lupus nephritides,    arthritis, immune complex disorders and autoimmune diseases,    systemic lupus, or lupus erythematosus;-   (iv) ischemia/reperfusion injury (FR injury), myocardial infarction,    myocarditis, post-ischemic reperfusion conditions, balloon    angioplasty, atherosclerosis, post-pump syndrome in cardiopulmonary    bypass or renal bypass, renal ischemia, mesenteric artery    reperfusion after aortic reconstruction, antiphospholipid syndrome,    autoimmune heart disease, ischemia-reperfusion injuries, obesity, or    diabetes;-   (v) Alzheimer's dementia, stroke, schizophrenia, traumatic brain    injury, trauma, Parkinson's disease, epilepsy, transplant rejection,    prevention of fetal loss, biomaterial reactions (e.g. in    hemodialysis, implants), hyperacute allograft rejection, xenograft    rejection, transplantation, psoriasis, burn injury, thermal injury    including burns or frostbite;-   (vi) asthma, allergy, acute respiratory distress syndrome (ARDS),    cystic fibrosis, adult respiratory distress syndrome, dyspnea,    hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema,    pulmonary embolisms and infarcts, pneumonia, fibrogenic dust    diseases, inert dusts and minerals (e.g., silicon, coal dust,    beryllium, and asbestos), pulmonary fibrosis, organic dust diseases,    chemical injury (due to irritant gases and chemicals, e.g.,    chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen    dioxide, ammonia, and hydrochloric acid), smoke injury, thermal    injury (e.g., burn, freeze), bronchoconstriction, hypersensitivity    pneumonitis, parasitic diseases, Goodpasture's Syndrome    (anti-glomerular basement membrane nephritis), pulmonary vasculitis,    Pauci-immune vasculitis, or immune complex-associated inflammation.

In one embodiment, a method for the treatment of paroxysmal nocturnalhemoglobinuria (PNH) is provided that includes the administration of aneffective amount of a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of age-related maculardegeneration (AMD) is provided that includes the administration of aneffective amount of a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of rheumatoidarthritis is provided that includes the administration of an effectiveamount of a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of multiple sclerosisis provided that includes the administration of an effective amount of acompound selected from Table 2 or Table 3, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier.

In another embodiment, a method for the treatment of myasthenia gravisis provided that includes the administration of an effective amount of acompound selected from Table 2 or Table 3, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier.

In another embodiment, a method for the treatment of atypical hemolyticuremic syndrome (aHUS) is provided that includes the administration ofan effective amount of a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of C3glomerulonephritis is provided that includes the administration of aneffective amount of a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of abdominal aorticaneurysm is provided that includes the administration of an effectiveamount of a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of neuromyelitisoptica (NMO) is provided that includes the administration of aneffective amount of a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In some embodiments, the present invention provides methods of treatingor preventing an inflammatory disorder or a complement related disease,by administering to a host in need thereof an effective amount of acompound selected from Table 2 or Table 3 of the invention. In someembodiments, the present invention provides methods of treating orpreventing an inflammatory disorder more generally, an immune disorder,autoimmune disorder, or complement Factor D related disorder, byproviding an effective amount of a compound or pharmaceuticallyacceptable salt of a compound selected from Table 2 or Table 3 topatient with a Factor D mediated inflammatory disorder. A compoundselected from Table 2 or Table 3 may be provided as the only activeagent or may be provided together with one or more additional activeagents.

In one embodiment, a method for the treatment of a disorder associatedwith a dysfunction in the complement cascade is provided that includesthe administration of an effective amount of a compound selected fromTable 2 or Table 3, or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutically acceptable carrier. In one embodiment,a method of inhibiting activation of the alternative complement pathwayin a host is provided that includes the administration of an effectiveamount of a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In one embodiment, a method ofmodulating Factor D activity in a host is provided that includes theadministration of an effective amount of a compound selected from Table2 or Table 3, or a pharmaceutically acceptable salt thereof, optionallyin a pharmaceutically acceptable carrier.

In an additional alternative embodiment, the compound selected fromTable 2 or Table 3, or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutically acceptable carrier is used in thetreatment of an autoimmune disorder.

The complement pathway enhances the ability of antibodies and phagocyticcells to clear microbes and damaged cells from the body. It is part ofthe innate immune system and in healthy individuals is an essentialprocess. Inhibiting the complement pathway will decrease the body'simmune system response. Therefore, it is an object of the presentinvention to treat autoimmune disorders by administering an effectivedoes of a compound of Table 2 or Table 3, or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier, to a host in need thereof.

In one embodiment the autoimmune disorder is caused by activity of thecomplement system. In one embodiment the autoimmune disorder is causedby activity of the alternative complement pathway. In one embodiment theautoimmune disorder is caused by activity of the classical complementpathway. In another embodiment the autoimmune disorder is caused by amechanism of action that is not directly related to the complementsystem, such as the over-proliferation of T-lymphocytes or theover-production of cytokines.

Non-limiting examples of autoimmune disorders include: allograftrejection, autoimmune thyroid diseases (such as Graves' disease andHashimoto's thyroiditis), autoimmune uveoretinitis, giant cellarteritis, inflammatory bowel diseases (including Crohn's disease,ulcerative colitis, regional enteritis, granulomatous enteritis, distalileitis, regional ileitis, and terminal ileitis), diabetes, multiplesclerosis, pernicious anemia, psoriasis, rheumatoid arthritis,sarcoidosis, and scleroderma.

In one embodiment, a compound selected from Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier, is used in the treatment of lupus.Non-limiting examples of lupus include lupus erythematosus, cutaneouslupus, discoid lupus erythematosus, chilblain lupus erythematosus, lupuserythematosus-lichen planus overlap syndrome.

Lupus erythematosus is a generic category of disease that includes bothsystemic and cutaneous disorders. The systemic form of the disease canhave cutaneous as well as systemic manifestations. However, there arealso forms of the disease that are only cutaneous without systemicinvolvement. For example, SLE is an inflammatory disorder of unknownetiology that occurs predominantly in women, and is characterized byarticular symptoms, butterfly erythema, recurrent pleurisy,pericarditis, generalized adenopathy, splenomegaly, as well as CNSinvolvement and progressive renal failure. The sera of most patients(over 98%) contain antinuclear antibodies, including anti-DNAantibodies. High titers of anti-DNA antibodies are essentially specificfor SLE. Conventional treatment for this disease has been theadministration of corticosteroids or immunosuppressants.

There are three forms of cutaneous lupus: chronic cutaneous lupus (alsoknown as discoid lupus erythematosus or DLE), subacute cutaneous lupus,and acute cutaneous lupus. DLE is a disfiguring chronic disorderprimarily affecting the skin with sharply circumscribed macules andplaques that display erythema, follicular plugging, scales,telangiectasia and atrophy. The condition is often precipitated by sunexposure, and the early lesions are erythematous, round scaling papulesthat are 5 to 10 mm in diameter and display follicular plugging. DLElesions appear most commonly on the cheeks, nose, scalp, and ears, butthey may also be generalized over the upper portion of the trunk,extensor surfaces of the extremities, and on the mucous membranes of themouth. If left untreated, the central lesion atrophies and leaves ascar. Unlike SLE, antibodies against double-stranded DNA (e.g.,DNA-binding test) are almost invariably absent in DLE.

Multiple sclerosis is an autoimmune demyelinating disorder that isbelieved to be T lymphocyte dependent. MS generally exhibits arelapsing-remitting course or a chronic progressive course. The etiologyof MS is unknown, however, viral infections, genetic predisposition,environment, and autoimmunity all appear to contribute to the disorder.Lesions in MS patients contain infiltrates of predominantly T lymphocytemediated microglial cells and infiltrating macrophages. CD4+ Tlymphocytes are the predominant cell type present at these lesions. Thehallmark of the MS lesion is plaque, an area of demyelination sharplydemarcated from the usual white matter seen in MM scans. Histologicalappearance of MS plaques varies with different stages of the disease. Inactive lesions, the blood-brain barrier is damaged, thereby permittingextravasation of serum proteins into extracellular spaces. Inflammatorycells can be seen in perivascular cuffs and throughout white matter.CD4+ T-cells, especially Th1, accumulate around postcapillary venules atthe edge of the plaque and are also scattered in the white matter. Inactive lesions, up-regulation of adhesion molecules and markers oflymphocyte and monocyte activation, such as IL2-R and CD26 have alsobeen observed. Demyelination in active lesions is not accompanied bydestruction of oligodendrocytes. In contrast, during chronic phases ofthe disease, lesions are characterized by a loss of oligodendrocytes andhence, the presence of myelin oligodendrocyte glycoprotein (MOG)antibodies in the blood.

Diabetes can refer to either type 1 or type 2 diabetes. In oneembodiment a compound of Table 2 or Table 3 or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier, is provided at an effective dose to treat a patient with type 1diabetes. In one embodiment a compound of Table 2 or Table 3, or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier, is provided at an effective dose totreat a patient with type 2 diabetes.

Type 1 diabetes is an autoimmune disease. An autoimmune disease resultswhen the body's system for fighting infection (the immune system) turnsagainst a part of the body. The pancreas then produces little or noinsulin.

V. Combination Therapy

In additional embodiments, an effective amount of an active compound orits salt or composition as described herein may be provided incombination or alternation with or preceded by, concomitant with orfollowed by, an effective amount of at least one additional therapeuticagent, for example, for treatment of a disorder listed herein.Non-limiting examples of additional therapeutic agents for suchcombination therapy are provided below.

In one embodiment, an effective amount of an active compound or its saltor composition as described herein may be provided in combination oralternation with an effective amount of at least one additionalinhibitor of the complement system or a second active compound with adifferent biological mechanism of action. In the description below andherein generally, whenever any of the terms referring to an activecompound or its salt or composition as described herein are used, itshould be understood that pharmaceutically acceptable salts, prodrugs orcompositions are considered included, unless otherwise stated orinconsistent with the text.

In non-limiting embodiments, an active compound or its salt orcomposition as described herein may be provided together with a proteaseinhibitor, a soluble complement regulator, a therapeutic antibody(monoclonal or polyclonal), complement component inhibitor, receptoragonist, or siRNA.

In other embodiments, an active compound described herein isadministered in combination or alternation with an antibody againsttumor necrosis factor (TNF), including but not limited to infliximab(Remicade), adalimumab, certolizumab, golimumab, or a receptor fusionprotein such as etanercept (Embrel).

In another embodiment, an active compound as described herein can beadministered in combination or alternation with an anti-CD20 antibody,including but not limited to rituximab (Rituxan), adalimumab (Humira),ofatumumab (Arzerra), tositumomab (Bexxar), obinutuzumab (Gazyva), oribritumomab (Zevalin).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with an anti-IL6 antibody,including but not limited to tocilizumab (Actemra) and siltuximab(Sylvant).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with an IL17 inhibitor,including but not limited to secukibumab (Cosentyx).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with a p40 (IL12/IL23)inhibitor, including but not limited to ustekinumab (Stelara).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with an IL23 inhibitor,including but not limited to risankizumab.

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with an anti-interferon αantibody, for example but not limited to sifalimumab.

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with a kinase inhibitor,for example but not limited to a JAK1/JAK3 inhibitor, for example butnot limited to tofacitinib (Xelianz). In an alternative embodiment, anactive compound as described herein can be administered in combinationor alteration with a JAK1/JAK2 inhibitor, for example but not limited tobaracitibib.

In another embodiment, an active compound as described herein can beadministered in combination or alternation with an immune checkpointinhibitor. Non-limiting examples of checkpoint inhibitors are anti-PD-1or anti-PDL1 antibodies (for example, Nivolumab, Pembrolizumab,Pidilizumab and Atezolizumab) and anti-CTLA4 antibodies (Ipilimumab andTremelimumab).

Non-limiting examples of active agents that can be used in combinationwith active compounds described herein are:

Protease inhibitors: plasma-derived C1-INH concentrates, for exampleCetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze®;recombinant human C1-inhibitors, for example Rhucin®; ritonavir(Norvir®, Abbvie, Inc.);

Soluble complement regulators: Soluble complement receptor 1 (TP10)(Avant Immunotherapeutics); sCR1-sLex/TP-20 (Avant Immunotherapeutics);MLN-2222/CAB-2 (Millenium Pharmaceuticals); Mirococept (InflazymePharmaceuticals);

Therapeutic antibodies: Eculizumab/Soliris (Alexion Pharmaceuticals);Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234(Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (GenmabA/S);

Complement component inhibitors: Compstatin/POT-4 (PotentiaPharmaceuticals); ARC1905 (Archemix);

Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717(Jerini);

Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals).

Imides and glutarimide derivatives such as thalidomide, lenalidomide,pomalidomide;

Additional non-limiting examples that can be used in combination oralternation with an active compound or its salt or composition asdescribed herein include the following.

Non-limiting examples of potential therapeutics for combination therapyName Target Company Class of Molecule LFG316 C5 Novartis/MorphosysMonoclonal antibody 4(1MEW)APL-1,APL-2 C3/C3b Apella Compstatin Family4(1MeW)POT-4 C3/C3b Potentia Compstatin Family Anti-C5 siRNA C5 AlnylamSi-RNA Anti-FB siRNA CFB Alnylam SiRNA ARC1005 C5 Novo Nordisk AptamersATA C5 N.A. Chemical Coversin C5 Volution Immuno- Small animal proteinPharmaceuticals CP40/AMY-101,PEG- C3/C3b Amyndas Compstatin Family Cp40CRIg/CFH CAP C3 NA CFH-based protein convertase Cynryze C1n/C1sViroPharma/Baxter Human purified protein FCFD4514S CFD Genentech/RocheMonoclonal antibody H17 C3 EluSys Therapeutics Monoclonal antibody(C3b/iC3b) Mini-CFH CAP C3 Amyndas CFH-based protein convertaseMirococept (APT070) CAP and CCP NA CR1-based protein C3 Mubodine C5Adienne Monoclonal antibody RA101348 C5 Rapharma Small molecule sCR1(CDX-1135) CAP and CP Celldex CR1-based protein C3 SOBI002 C5 SwedishOrphan Affibody Biovitrum SOMAmers C5 SomaLogic Aptamers SOMAmers CFBand CFD SomaLogic Aptamers (SELEX) TA106 CFB Alexion Monoclonal antibodyPharmaceuticals TNT003 C1s True North Monoclonal antibody TT30 (CR2/CFH)CAP C3 Alexion CFH-based protein convertase TT32 (CR2/CR1) CAP and CCPAlexion CR1-based protein C3 Pharmaceuticals Nafamostat (FUT-175, C1s,CFD, Torri Pharmaceuticals Small molecule Futhan) other proteases OMS721MASP-2 Omeros Monoclonal antibody OMS906 MASP-2 Omeros Monoclonalantibody Bikaciomab, NM9308 CFB Novelmed Monoclonal antibody NM9401Properdin Novelmed Monoclonal antibody CVF, HC-1496 C3 InCodeRecombinant peptide ALXN1102/ALXN1103 C3-conv, C3b Alexion Regulator(TT30) Pharmaceuticals rFH C3-conv, C3b Optherion Regulator 5C6, AMY-301CFH Amyndas Regulator Erdigna C5 Adienne Pharma Antibody ARC1905 C5Opthotech Monoclonal Antibody MEDI7814 C5/C5a MedImmune MonoclonalAntibody NOX-D19 C5a Noxxon Aptamer (Spiegelmer) IFX-1, CaCP29 C5aInflaRx Monoclonal Antibody PMX53, PMX205 C5aR Cephalon, TevaPeptidomimetic CCX168 C5aR ChemoCentryx Small molecule ADC-1004 C5aRAlligator Bioscience Small molecule Anti-C5aR-151, C5aR Novo NordiskMonoclonal Antibody NN8209; Anti-C5aR- 215, NN8210 Imprime PGG CR3Biothera Soluble beta-glucan

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided together with a compound that inhibitsan enzyme that metabolizes an administered protease inhibitor. In oneembodiment, a compound or salt may be provided together with ritonavir.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a complement C5inhibitor or C5 convertase inhibitor. In another embodiment, an activecompound or its salt or composition as described herein may be providedin combination with eculizumab, a monoclonal antibody directed to thecomplement factor C5 and manufactured and marketed by AlexionPharmaceuticals under the tradename Soliris. Eculizumab has beenapproved by the U.S. FDA for the treatment of PNH and aHUS.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided together with a compound that inhibitscomplement factor D. In one embodiment of the invention, an activecompound or its salt or composition as described herein as describedherein can be used in combination or alternation with a compounddescribed in Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled“Compounds useful in the complement, coagulate and kallikrein pathwaysand method for their preparation” describes fused bicyclic ringcompounds that are potent inhibitors of Factor D; Novartis PCT patentpublication WO2012/093101 titled “Indole compounds or analogues thereofuseful for the treatment of age-related macular degeneration” describescertain Factor D inhibitors; Novartis PCT patent publicationsWO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054,WO2014/002057, WO2014/002058, WO2014/002059, WO2014/005150,WO2014/009833, WO 2013/164802, WO 2015/009616, WO 2015/066241,Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Openchain prolyl urea-related modulators of androgen receptor function”;Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amidederivatives and nociceptin antagonists”; Ferring B. V. and YamanouchiPharmaceutical Co. LTD. PCT patent publication WO1993/020099 titled “CCKand/or gastrin receptor ligands”; Alexion Pharmaceuticals PCT patentpublication WO1995/029697 titled “Methods and compositions for thetreatment of glomerulonephritis and other inflammatory diseases”; orAchillion Pharmaceuticals filed PCT Patent Application No.PCT/US2015/017523 and U.S. patent application Ser. No. 14/631,090 titled“Alkyne Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017538 and U.S. patent applicationSer. No. 14/631,233 titled “Amide Compounds for Treatment of ComplementMediated Disorders”; PCT Patent Application No. PCT/US2015/017554 andU.S. patent application Ser. No. 14/631,312 titled “Amino Compounds forTreatment of Complement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017583 and U.S. patent application Ser. No. 14/631,440 titled“Carbamate, Ester, and Ketone Compounds for Treatment of ComplementMediated Disorders”; PCT Patent Application No. PCT/US2015/017593 andU.S. patent application Ser. No. 14/631,625 titled “Aryl, Heteroaryl,and Heterocyclic Compounds for Treatment of Complement MediatedDisorders”; PCT Patent Application No. PCT/US2015/017597 and U.S. patentapplication Ser. No. 14/631,683 titled “Ether Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017600 and U.S. patent application Ser. No. 14/631,785 titled“Phosphonate Compounds for Treatment of Complement Mediated Disorders”;and PCT Patent Application No. PCT/US2015/017609 and U.S. patentapplication Ser. No. 14/631,828 titled “Compounds for Treatment ofComplement Mediated Disorders.”

In one embodiment, an active compound or its salt or composition asdescribed herein is administered in combination with ananti-inflammatory drug, antimicrobial agent, anti-angiogenesis agent,immunosuppressant, antibody, steroid, ocular antihypertensive drug orcombinations thereof. Examples of such agents include amikacin,anecortane acetate, anthracenedione, anthracycline, an azole,amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol,chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazolecephalosporin, corticosteroids, dexamethasone, desamethazone, econazole,eftazidime, epipodophyllotoxin, fluconazole, flucytosine,fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides,imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin,macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin,neomycin, nystatin, ofloxacin, polyhexamethylene biguanide,prednisolone, prednisolone acetate, pegaptanib, platinum analogues,polymicin B, propamidine isethionate, pyrimidine nucleoside,ranibizumab, squalamine lactate, sulfonamides, triamcinolone,triamcinolone acetonide, triazoles, vancomycin, anti-vascularendothelial growth factor (VEGF) agents, VEGF antibodies, VEGF antibodyfragments, vinca alkaloid, timolol, betaxolol, travoprost, latanoprost,bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine,ciprofloxacin, azithromycin, gentamycin, tobramycin, cefazolin,voriconazole, gancyclovir, cidofovir, foscarnet, diclofenac, nepafenac,ketorolac, ibuprofen, indomethacin, fluoromethalone, rimexolone,anecortave, cyclosporine, methotrexate, tacrolimus and combinationsthereof.

In one embodiment of the present invention, an active compound or itssalt or composition as described herein can be administered incombination or alternation with at least one immunosuppressive agent.The immunosuppressive agent as non-limiting examples, may be acalcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTORinhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus(RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus,biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine,campath 1H, a S1P receptor modulator, e.g. fingolimod or an analoguethereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof,e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil(CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g,etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,tocilizumab (Actemra), siltuximab (Sylvant), secukibumab (Cosentyx),ustekinumab (Stelara), risankizumab, sifalimumab, aspirin and ibuprofen.

Examples of anti-inflammatory agents include methotrexate,dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate,fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate,medrysone, prednisolone acetate, prednisolone sodium phosphate,difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate,lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam,meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenacsodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac,flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib,glucocorticoids, diclofenac, and any combination thereof. In oneembodiment, an active compound or its salt or composition as describedherein is combined with one or more non-steroidal anti-inflammatorydrugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib(Celebrex), sulindac (Clinoril), oxaprozin (Daypro), sal salate(Disalcid), difluni sal (Dolobid), piroxicam (Feldene), indomethacin(Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn),nabumetone (Relafen), ketorolac tromethamine (Toradol),naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), andcombinations thereof.

In one embodiment, an active compound or its salt or composition asdescribed herein is administered in combination or alteration with anomega-3 fatty acid or a peroxisome proliferator-activated receptor(PPARs) agonist. Omega-3 fatty acids are known to reduce serumtriglycerides by inhibiting DGAT and by stimulating peroxisomal andmitochondrial beta oxidation. Two omega-3 fatty acids, eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA), have been found to have highaffinity for both PPAR-alpha and PPAR-gamma. Marine oils, e.g., fishoils, are a good source of EPA and DHA, which have been found toregulate lipid metabolism. Omega-3 fatty acids have been found to havebeneficial effects on the risk factors for cardiovascular diseases,especially mild hypertension, hypertriglyceridemia and on thecoagulation factor VII phospholipid complex activity. Omega-3 fattyacids lower serum triglycerides, increase serum HDL-cholesterol, lowersystolic and diastolic blood pressure and the pulse rate, and lower theactivity of the blood coagulation factor VII-phospholipid complex.Further, omega-3 fatty acids seem to be well tolerated, without givingrise to any severe side effects. One such form of omega-3 fatty acid isa concentrate of omega-3, long chain, polyunsaturated fatty acids fromfish oil containing DHA and EPA and is sold under the trademark Omacor®.Such a form of omega-3 fatty acid is described, for example, in U.S.Pat. Nos. 5,502,077, 5,656,667 and 5,698,594, the disclosures of whichare incorporated herein by reference.

Peroxisome proliferator-activated receptors (PPARs) are members of thenuclear hormone receptor superfamily ligand-activated transcriptionfactors that are related to retinoid, steroid and thyroid hormonereceptors. There are three distinct PPAR subtypes that are the productsof different genes and are commonly designated PPAR-alpha,PPAR-beta/delta (or merely, delta) and PPAR-gamma. General classes ofpharmacological agents that stimulate peroxisomal activity are known asPPAR agonists, e.g., PPAR-alpha agonists, PPAR-gamma agonists andPPAR-delta agonists. Some pharmacological agents are combinations ofPPAR agonists, such as alpha/gamma agonists, etc., and some otherpharmacological agents have dual agonist/antagonist activity. Fibratessuch as fenofibrate, bezafibrate, clofibrate and gemfibrozil, arePPAR-alpha agonists and are used in patients to decrease lipoproteinsrich in triglycerides, to increase HDL and to decrease atherogenic-denseLDL. Fibrates are typically orally administered to such patients.Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester, has been known for many years as a medicinallyactive principle because of its efficacy in lowering blood triglycerideand cholesterol levels.

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa host in need thereof an effective amount of an active compound or itssalt or composition as described herein in combination with an anti-VEGFagent. Non-limiting examples of anti-VEGF agents include, but are notlimited to, aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab(Lucentis®: Genentech and Novartis); and pegaptanib (Macugen®; OSIPharmaceuticals and Pfizer); Bevacizumab (Avastin; Genentech/Roche);anecortane acetate, squalamine lactate, and corticosteroids, including,but not limited to, triamcinolone acetonide.

In one embodiment, the present invention provides a method of treatingor preventing paroxysmal nocturnal hemoglobinuria (PNH) by administeringto a host in need thereof an effective amount of an active compound orits salt or composition as described herein with an additional inhibitorof the complement system or another active compound with a differentbiological mechanism of action. In another embodiment, the presentinvention provides a method of treating or preventing paroxysmalnocturnal hemoglobinuria (PNH) by administering to a host in needthereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation witheculizumab. In another embodiment, the present invention provides amethod of treating or preventing paroxysmal nocturnal hemoglobinuria(PNH) by administering to a host in need thereof an effective amount ofan active compound or its salt or composition as described herein incombination or alternation with CP40. In one embodiment, the additionalagent is PEGylated-CP40. CP40 is a peptide inhibitor that shows a strongbinding affinity for C3b and inhibits hemolysis of paroxysmal nocturnalhemoglobinuria (PNH) erythrocytes.

In one embodiment, the present invention provides a method of treatingor preventing rheumatoid arthritis by administering to a host in needthereof an effective amount of a composition comprising an activecompound or its salt or composition as described herein in combinationor alternation with an additional inhibitor of the complement system, oran active agent that functions through a different mechanism of action.In another embodiment, the present invention provides a method oftreating or preventing rheumatoid arthritis by administering to a hostin need thereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation withmethotrexate. In certain embodiments, an active compound or its salt orcomposition as described herein is administered in combination oralternation with at least one additional therapeutic agent selectedfrom: salicylates including aspirin (Anacin, Ascriptin, Bayer Aspirin,Ecotrin) and salsalate (Mono-Gesic, Salgesic); nonsteroidalanti-inflammatory drugs (NSAIDs); nonselective inhibitors of thecyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac(Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis),naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine),indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam(Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors includingCelecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs),including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), goldsalts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine(Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex),penicillamine (Cuprimine), and sulfasalazine (Azulfidine); biologicdrugs including abatacept (Orencia), etanercept (Enbrel), infliximab(Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroidsincluding betamethasone (Celestone Soluspan), cortisone (Cortone),dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol),prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), andtriamcinolone (Aristocort); gold salts, including Auranofin (Ridaura);Aurothioglucose (Solganal); Aurolate; Myochrysine; or any combinationthereof.

In one embodiment, the present invention provides a method of treatingor preventing multiple sclerosis by administering to a host in needthereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation with anadditional inhibitor of the complement system, or an active agent thatfunctions through a different mechanism of action. In anotherembodiment, the present invention provides a method of treating orpreventing multiple sclerosis by administering to a host in need thereofan effective amount of an active compound or its salt or composition asdescribed herein in combination or alternation with a corticosteroid.Examples of corticosteroids include, but are not limited to, prednisone,dexamethasone, solumedrol, and methylprednisolone. In one embodiment, anactive compound or its salt or composition as described herein iscombined with at least one anti-multiple sclerosis drug, for example,selected from: Aubagio (teriflunomide), Avonex (interferon beta-1a),Betaseron (interferon beta-1b), Copaxone (glatiramer acetate), Extavia(interferon beta-1b), Gilenya (fingolimod), Lemtrada (alemtuzumab),Novantrone (mitoxantrone), Plegridy (peginterferon beta-1a), Rebif(interferon beta-1a), Tecfidera (dimethyl fumarate), Tysabri(natalizumab), Solu-Medrol (methylprednisolone), High-dose oralDeltasone (prednisone), H.P. Acthar Gel (ACTH), or a combinationthereof.

In one embodiment, an active compound or its salt or composition asdescribed herein is useful in a combination with another pharmaceuticalagent to ameliorate or reduce a side effect of the agent. For example,in one embodiment, an active compound or its salt or composition asdescribed herein may be used in combination with adoptive cell transfertherapies to reduce an associated inflammatory response associated withsuch therapies, for example, a cytokine mediated response such ascytokine release syndrome. In one embodiment, the adoptive cell transfertherapy includes the use of a chimeric antigen receptor T-Cell (CAR T).In one embodiment, the adoptive cell transfer therapy includes the useof a chimeric antigen receptor T-Cell (CAR T) or a dendritic cell totreat a hematologic or solid tumor, for example, a B-cell relatedhematologic cancer. In one embodiment, the hematologic or solid tumor isacute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreaticcancer, glioblastoma, or a cancer that expresses CD19.

In an additional alternative embodiment, an active compound or its saltor composition as described herein may be provided in combination witheculizumab for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis,AMD, CAD, chronic hemolysis, neuromyelitis optica, or transplantationrejection. In one embodiment, an active compound or its salt orcomposition as described herein may be provided in combination withcompstatin or a compstatin derivative for the treatment of PNH, aHUSs,STEC-HUS, ANCA-vasculitis, AMD, CAD, chronic hemolysis, neuromyelitisoptica, or transplantation rejection.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with rituxan for thetreatment of a complement mediated disorder. In one embodiment, thecomplement mediated disorder is, for example, rheumatoid arthritis,Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis), andMicroscopic Polyangiitis (MPA). In one embodiment, the disorder isLupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with cyclophosphamidefor the treatment of a complement mediated disorder. In one embodiment,the disorder is an autoimmune disease. In one embodiment, the complementmediated disorder is, for example, rheumatoid arthritis, Granulomatosiswith Polyangiitis (GPA) (Wegener's Granulomatosis), and MicroscopicPolyangiitis (MPA). In one embodiment, the disorder is Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein is dosed in combination with a conventional DLEtreatment for the treatment of lupus to a host in need thereof.

Examples of conventional DLE treatments include topical corticosteroidointments or creams, such as triamcinolone acetonide, fluocinolone,flurandrenolide, betamethasone valerate, or betamethasone dipropionate.Resistant plaques can be injected with an intradermal corticosteroid.Other potential DLE treatments include calcineurin inhibitors such aspimecrolimus cream or tacrolimus ointment. Particularly resistant casescan be treated with systemic antimalarial drugs, such ashydroxychloroquine (PLAQUENIL).

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with methotrexate forthe treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with azathioprine forthe treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a non-steroidalanti-inflammatory drug for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a corticosteroidfor the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a belimumab(Benlysta) for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with hydroxychloroquine(Plaquenil) for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with sifalimumab for thetreatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with OMS721 (Omeros) forthe treatment of a complement mediated disorder. In one embodiment, anactive compound or its salt or composition as described herein may beprovided in combination with OMS906 (Omeros) for the treatment of acomplement mediated disorder. In one embodiment, the complement mediateddisorder is, for example, thrombotic thrombocytopenic purpura (TTP) oraHUS.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with ananti-inflammatory agent, immunosuppressive agent, or anti-cytokine agentfor the treatment or prevention of cytokine or inflammatory reactions inresponse to the administration of biotherapeutics (e.g. adoptive T-celltherapy (ACT) such as CAR T-cell therapy, or monoclonal antibodytherapy). In one embodiment, an active compound or its salt orcomposition as described herein may be provided in combination with acorticosteroid, for example prednisone, dexamethasone, solumedrol, andmethylprednisolone, and/or anti-cytokine compounds targeting, e.g.,IL-4, IL-10, IL-11, IL-13 and TGFβ. In one embodiment, an activecompound or its salt or composition as described herein may be providedin combination with an anti-cytokine inhibitor including, but are notlimited to, adalimumab, infliximab, etanercept, protopic, efalizumab,alefacept, anakinra, siltuximab, secukibumab, ustekinumab, golimumab,and tocilizumab, or a combination thereof. Additional anti-inflammatoryagents that can be used in combination with an active compound or itssalt or composition as described herein include, but are not limited to,non-steroidal anti-inflammatory drug(s) (NSAIDs); cytokine suppressiveanti-inflammatory drug(s) (CSAIDs); CDP-571/BAY-10-3356 (humanizedanti-TNFα antibody; Celltech/Bayer); cA2/infliximab (chimeric anti-TNFαantibody; Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF receptor-IgGfusion protein; Immunex); 55 kdTNF-IgG (55 kD TNF receptor-IgG fusionprotein; Hoffmann-LaRoche); IDEC-CE9.1/SB 210396 (non-depletingprimatized anti-CD4 antibody; IDEC/SmithKline); DAB 486-IL-2 and/or DAB389-IL-2 (IL-2 fusion proteins; Seragen); Anti-Tac (humanizedanti-IL-2Rα; Protein Design Labs/Roche); IL-4 (anti-inflammatorycytokine; DNAX/Schering); IL-10 (SCH 52000; recombinant IL-10,anti-inflammatory cytokine; DNAX/Schering); IL-4; IL-10 and/or IL-4agonists (e.g., agonist antibodies); IL-1RA (IL-1 receptor antagonist;Synergen/Amgen); anakinra (Kineret®/Amgen); TNF-bp/s-TNF (soluble TNFbinding protein); R973401 (phosphodiesterase Type IV inhibitor); MK-966(COX-2 Inhibitor); Iloprost, leflunomide (anti-inflammatory and cytokineinhibiton); tranexamic acid (inhibitor of plasminogen activation); T-614(cytokine inhibitor); prostaglandin E1; Tenidap (non-steroidalanti-inflammatory drug); Naproxen (non-steroidal anti-inflammatorydrug); Meloxicam (non-steroidal anti-inflammatory drug); Ibuprofen(non-steroidal anti-inflammatory drug); Piroxicam (non-steroidalanti-inflammatory drug); Diclofenac (non-steroidal anti-inflammatorydrug); Indomethacin (non-steroidal anti-inflammatory drug);Sulfasalazine; Azathioprine; ICE inhibitor (inhibitor of the enzymeinterleukin-1β converting enzyme); zap-70 and/or lck inhibitor(inhibitor of the tyrosine kinase zap-70 or lck); TNF-convertaseinhibitors; anti-IL-12 antibodies; anti-IL-18 antibodies;interleukin-11; interleukin-13; interleukin-17 inhibitors; gold;penicillamine; chloroquine; chlorambucil; hydroxychloroquine;cyclosporine; cyclophosphamide; anti-thymocyte globulin; anti-CD4antibodies; CD5-toxins; orally-administered peptides and collagen;lobenzarit disodium; Cytokine Regulating Agents (CRAB) HP228 and HP466(Houghten Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioateoligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); solublecomplement receptor 1 (TP10; T Cell Sciences, Inc.); prednisone;orgotein; glycosaminoglycan polysulphate; minocycline; anti-IL2Rantibodies; marine and botanical lipids (fish and plant seed fattyacids); auranofin; phenylbutazone; meclofenamic acid; flufenamic acid;intravenous immune globulin; zileuton; azaribine; mycophenolic acid(RS-61443); tacrolimus (FK-506); sirolimus (rapamycin); amiprilose(therafectin); cladribine (2-chlorodeoxyadenosine).

In a specific embodiment, an active compound or its salt or compositionas described herein may be provided in combination with a corticosteroidfor the treatment or prevention of cytokine or inflammatory reactions inresponse to the administration of biotherapeutics. In anotherembodiment, an active compound or its salt or composition as describedherein may be provided in combination with etarnercept for the treatmentor prevention of cytokine or inflammatory reactions in response to theadministration of biotherapeutics. In another embodiment, an activecompound or its salt or composition as described herein may be providedin combination with tocilizumab for the treatment or prevention ofcytokine or inflammatory reactions in response to the administration ofbiotherapeutics. In another embodiment, an active compound or its saltor composition as described herein may be provided in combination withetarnercept and tocilizumab for the treatment or prevention of cytokineor inflammatory reactions in response to the administration ofbiotherapeutics. In another embodiment, an active compound or its saltor composition as described herein may be provided in combination withinfliximab for the treatment or prevention of cytokine or inflammatoryreactions in response to the administration of biotherapeutics. Inanother embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with golimumab for thetreatment or prevention of cytokine or inflammatory reactions inresponse to the administration of biotherapeutics.

VI. Combinations for Prophylactic or Concommitant Anti-Bacterial Therapy

In one aspect of the present invention, a method is provided fortreating a host in need thereof that comprises administering aneffective amount of a prophylactic anti-bacterial vaccine prior toadministration of an active compound or its salt or composition for anyof the disorders described herein. In another aspect of the presentinvention, a method is provided for treating a host in need thereof thatcomprises administering an effective amount of a prophylacticanti-bacterial drug, such as a pharmaceutical drug, prior toadministration of an active compound or its salt or composition for anyof the disorders described herein. In one aspect of the presentinvention, a method is provided for treating a host in need thereof thatcomprises administering an effective amount of an anti-bacterial vaccineafter administration of an active compound or its salt or compositionfor any of the disorders described herein. In another aspect of thepresent invention, a method is provided for treating a host in needthereof that comprises administering an effective amount of ananti-bacterial drug, such as a pharmaceutical drug, after administrationof an active compound or its salt or composition for any of thedisorders described herein. In one embodiment, the disorder is PNH oraHUS. In one embodiment, the host has received an organ or other tissueor biological fluid transplant. In one embodiment, the host is alsoadministered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a hostconcomitantly with the prophylactic administration of a vaccine againsta bacterial infection. In one embodiment, the complement mediateddisorder is PNH or aHUS. In one embodiment, the host has received anorgan or other tissue or biological fluid transplant. In one embodiment,the host is also administered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a host and, duringthe administration period of the compound or salt, a vaccine against abacterial infection is administered to the host. In one embodiment, thedisorder is PNH or aHUS. In one embodiment, the host has received anorgan or other tissue or biological fluid transplant. In one embodiment,the host is also administered eculizumab.

In one aspect of the present invention, the host is administered anactive compound or its salt or composition as described herein incombination with an antibiotic compound for the duration of factor Dinhibitor administration. In one embodiment, the disorder is PNH oraHUS. In one embodiment, the host has received an organ or other tissueor biological fluid transplant. In one embodiment, the host is alsoadministered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a host followingthe prophylactic administration of a vaccine against a bacterialinfection, and in combination with an antibiotic compound for theduration of factor D inhibitor administration. In one embodiment, thecomplement mediated disorder is PNH or aHUS. In one embodiment, the hosthas received an organ or other tissue or biological fluid transplant. Inone embodiment, the host is also administered eculizumab.

In one embodiment, the host, prior to receiving an active compound orits salt or composition as described herein, is vaccinated against abacterial infection caused by the bacterium Neisseria meningitidis. Inone embodiment, the host is vaccinated against a bacterial infectioncaused by the bacterium Haemophilus influenzae. In one embodiment, theHaemophilus influenzae is Haemophilus influenzae serotype B (Hib). Inone embodiment, the host is vaccinated against a bacterial infectioncaused by Streptococcus pneumoniae. In one embodiment, the host isvaccinated against a bacterial infection caused by the bacteriumNisseria meningitidis, Haemophilus influenzae, or Streptococcuspneumoniae, or a combination of one or more of Nisseria meningitidis,Haemophilus influenzae, or Streptococcus pneumoniae. In one embodiment,the host is vaccinated against a bacterial infection caused by thebacterium Nisseria meningitidis, Haemophilus influenzae, andStreptococcus pneumoniae.

In other embodiments, the host is vaccinated against a bacterialinfection caused by a bacterium selected from a Gram-negative bacterium.In one embodiment, the host is vaccinated against a bacterial infectioncaused by a bacterium selected from a Gram-positive bacterium. In oneembodiment, the host is vaccinated against a bacterial infection causedby the bacterium Nisseria meningitidis, Haemophilus influenzae, orStreptococcus pneunemoniae, or a combination of one or more of Nisseriameningitidis, Haemophilus influenzae, or Streptococcus pneumoniae, andone or more of, but not limited to, Bacillus anthracis, Bordetellapertussis, Clostridium tetani, Corynebacterium diphtheria, Coxiellaburnetii, Mycobacterium tuberculosis, Salmonella typhi, Vibrio cholerae,Anaplasma phagocytophilum, Ehrlichia ewingii, Ehrlichia chaffeensis,Ehrlichia canis, Neorickettsia sennetsu, Mycobacterium leprae, Borreliaburgdorferi, Borrelia mayonii, Borrelia afzelii, Borrelia garinii,Mycobacterium bovis, Staphylococcus aureus, Streptococcus pyogenes,Treponema pallidum, Francisella tularensis, Yersinia pestis,

In one embodiment, the host is vaccinated with one or more vaccinesselected from, but not limited to, typhoid vaccine, live (Vivotif BernaVaccine, PaxVax), typhoid Vi polysaccharide vaccine (Typhim Vi, Sanofi),pneumococcal 23-polyvalent vaccine, PCV13 (Pneumovax 23, Merck),pneumococcal 7-valent vaccine, PCV7 (Prevnar, Pfizer), pneumococcal13-valent vaccine, PCV13 (Prevnar 13, Pfizer), haemophilus b conjugate(prp-t) vaccine (ActHIB, Sanofi; Hibrix, GSK), haemophilus b conjugate(hboc) vaccine (HibTITER, Neuron Biotech), haemophilus b conjugate(prp-omp) vaccine (PedvaxHIB, Merck), haemophilus b conjugate (prp-t)vaccine/meningococcal conjugate vaccine (MenHibrix, GSK), haemophilus bconjugate (prp-t) vaccine/meningococcal conjugate vaccine/Hepatitis Bvaccine (Comvax, Merck), meningococcal polysaccharide vaccine (MenomuneA/C/Y/W-135, Sanofi), meningococcal conjugate vaccine/diphtheria CRM197conjugate (Menveo, GSK; Menactra, Sanofi), meningococcal group B vaccine(Bexsero, GSK; Trumenba, Pfizer), anthrax vaccine adsorbed (Biothrax,Emergent Biosolutions), tetanus toxoid (Te Anatoxal Berna, HendricksRegional Health), Bacillus Calmette and Guerin, live, intravesical(TheraCys, Sanofi; Tice BCG, Organon), cholera vaccine, live, oral(Vachora, Sanofi; Dukoral, SBL Vaccines; ShanChol, Shantha Biotec;Micromedex, Truven Health), tetanus toxoids and diphtheria absorbed(Tdap; Decavac, Sanofi; Tenivac, Sanofi; td, Massachusetts BiologicalLabs), diphtheria and tetanus toxois and pertussis (DTap; Daptacel,Sanofi; Infanrix, GSK; Tripedia, Sanofi), diphtheria and tetanus toxoisand pertussis/polio (Kinrix, GSK; Quadracel, Sanofi), diphtheria andtetanus toxois and pertussis tetanus/hepatitis B/polio (Pediarix, GSK),diphtheria and tetanus toxois and pertussis/polio, haemophilus influenzatybe b (Pentacel, Sanofi), and/or diphtheria, and pertussis (Tdap;Boostrix, GSK; Adacel, Sanofi), or a combination thereof.

As described above, a host receiving a compound of the present inventionto treat disorder is prophylactically administered an antibioticcompound in addition to a factor D inhibitor described herein. In oneembodiment, the host is administered an antibiotic compound for theduration of administration of the active compound to reduce thedevelopment of a bacterial infection. Antibiotic compounds forconcomitant administration with a factor D inhibitor described hereincan be any antibiotic useful in preventing or reducing the effect of abacterial infection. Antibiotics are well known in the art and include,but are not limited to, amikacin (Amikin), gentamicin (Garamycin),kanamycin (Kantrex), neomycin (Neo-Fradin), netilmicin (Netromycin),tobramycin (Nebcin), paromomycin (Humatin), streptomycin, spectinomycin(Trobicin), geldanamycin, herbimycin, rifaximin (Xifaxan), loracarbef(Lorabid), ertapenem (Invanz), doripenem (Doribax), imipenem/cilastatin(Primaxin), meropenem (Merrem), cefadroxil (Duricef), cefazolin (Ancef),cefalotin/cefalothin (Keflin), cephalexin (Keflex), cefaclor(Distaclor), cefamandole (Mandol), cefoxitin (Mefoxin), cefprozil(Cefzil), cefuroxime (Ceftin, Zinnat), cefixime (Cefspan), cefdinir(Omnicef, Cefdiel), cefditoren (Spectracef, Meiact), cefoperazone(Cefobid), cefotaxime (Claforan), cefpodoxime (Vantin) ceftazidime(Fortaz), ceftibuten (Cedax), ceftizoxime (Cefizox), ceftriaxone(Rocephin), cefepime (Maxipime), ceftaroline fosamil (Teflaro),ceftobiprole (Zeftera), teicoplanin (Targocid), vancomycin (Vancocin),telavancin (Vibativ), dalbavancin (Dalvance), oritavancin (Orbactiv),clindamycin (Cleocin), lincomycin (Lincocin), daptomycin (Cubicin),azithromycin (Zithromax, Sumamed, Xithrone), clarithromycin (Biaxin),dirithromycin (Dynabac), erythromycin (Erythocin, Erythroped),roxithromycin, troleandomycin (Tao), telithromycin (Ketek), spiramycin(Rovamycine), aztreonam (Azactam), furazolidone (Furoxone),nitrofurantoin (Macrodantin, Macrobid), linezolid (Zyvox), posizolid,radezolid, torezolid, amoxicillin (Novamox, Amoxil), ampicillin(Principen),azlocillin, carbenicillin (Geocillin), cloxacillin(Tegopen), dicloxacillin (Dynapen), flucloxacillin (Floxapen),mezlocillin (Mezlin), methicillin (Staphcillin), nafcillin(Unipen),oxacillin (Prostaphlin), penicillin G (Pentids),penicillin V(Veetids (Pen-Vee-K), piperacillin (Pipracil), penicillin G (Pfizerpen),temocillin (Negaban),ticarcillin (Ticar), amoxicillin/clavulanate(Augmentin), ampicillin/sulbactam (Unasyn), piperacillin/tazobactam(Zosyn), ticarcillin/clavulanate (Timentin),bacitracin, colistin(Coly-Mycin-S), polymyxin B, ciprofloxacin (Cipro, Ciproxin, Ciprobay),enoxacin (Penetrex), gatifloxacin (Tequin), gemifloxacin (Factive),levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox),nalidixic acid (NegGram), norfloxacin (Noroxin), ofloxacin (Floxin,Ocuflox), trovafloxacin (Trovan), grepafloxacin (Raxar), sparfloxacin(Zagam), temafloxacin (Omniflox), mafenide (Sulfamylon), sulfacetamide(Sulamyd, Bleph-10), sulfadiazine (Micro-Sulfon), silver sulfadiazine(Silvadene), sulfadimethoxine (Di-Methox, Albon), sulfamethizole(Thiosulfil Forte), sulfamethoxazole (Gantanol), sulfanilamide,sulfasalazine (Azulfidine), sulfisoxazole (Gantrisin),trimethoprim-sulfamethoxazole (Co-trimoxazole) (TMP-SMX) (Bactrim,Septra), sulfonamidochrysoidine (Prontosil), demeclocycline(Declomycin), doxycycline (Vibramycin), minocycline (Minocin),oxytetracycline (Terramycin), tetracycline (Sumycin, Achromycin V,Steclin), clofazimine (Lamprene), dapsone (Avlosulfon), capreomycin(Capastat), cycloserine (Seromycin), ethambutol (Myambutol), ethionamide(Trecator), isoniazid (I.N.H.), pyrazinamide (Aldinamide), rifampicin(Rifadin, Rimactane), rifabutin (Mycobutin), rifapentine (Priftin),streptomycin, arsphenamine (Salvarsan), chloramphenicol (Chloromycetin),fosfomycin (Monurol, Monuril), fusidic acid (Fucidin), metronidazole(Flagyl), mupirocin (Bactroban), platensimycin,quinupristin/dalfopristin (Synercid), thiamphenicol, tigecycline(Tigacyl), tinidazole (Tindamax Fasigyn), trimethoprim (Proloprim,Trimpex), and/or teixobactin, or a combination thereof.

In one embodiment, the host is administered a prophylactic antibioticselected from cephalosporin, for example, ceftriaxone or cefotaxime,ampicillin-sulbactam, Penicillin G, ampicillin, chloramphenicol,fluoroquinolone, aztreonam, levofloxacin, moxifloxacin, gemifloxacin,vancomycin, clindamycin, cefazolin, azithromycin, meropenem,ceftaroline, tigecycline, clarithromycin, moxifloxacin,trimethoprim/sulfamethoxazole, cefuroxime, axetil, ciprofloxacin,rifampin, minocycline, spiramycin, and cefixime, or a combination of twoor more thereof.

VII. Process of Preparation of Active Compounds Abbreviations

-   (Boc)20 di-tert-butyl dicarbonate-   CAN Acetonitrile-   AcOEt, EtOAc Ethyl acetate-   CH₃OH, MeOH Methanol-   CsF Cesium fluoride-   CuI Cuprous iodide-   DCM, CH₂Cl₂ Dichloromethane-   DIEA, DIPEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DMF N,N-dimethylformamide-   DMSO Dimethyl sulfoxide-   DPPA Diphenyl phosphoryl azide-   Et₃N, TEA Triethylamine-   EtOAc Ethylacetate-   EtOH Ethanol-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxide hexafluorophosphate-   HCl Hydrochloric acid-   ^(i)Pr₂Net N,N-diisopropylethylamine-   K₂CO₃ Potassium carbonate-   LiOH Lithium hydroxide-   MTBE Methyl tert-butylether-   Na₂SO₄ Sodium sulfate-   NaCl Sodium chloride-   NaH Sodium hydride-   NaHCO₃ Sodium bicarbonate-   NEt₃ Trimethylamine-   Pd(OAc)₂ Palaldium acetate-   Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)    ferrocene]dichloropalladium(II)-   Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) dichloride-   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)-Tetrakis-   Pd₂ (dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   PPh₃ Triphenylphosphine-   RT Room temperature-   tBuOK Potassium tert-butoxide-   TEA Trimethylamine-   TFA Trifluoroacetic acid-   Tf₂O Trifluoromethanesulfonic anhydride-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TMSBr Bromotrimethylsilane-   t_(R) Retention time-   Zn (CN)₂ Zinc cyanide    General Methods

All nonaqueous reactions were performed under an atmosphere of dry argonor nitrogen gas using anhydrous solvents. The progress of reactions andthe purity of target compounds were determined using one of the twoliquid chromatography (LC) methods listed below. The structure ofstarting materials, intermediates, and final products was confirmed bystandard analytical techniques, including NMR spectroscopy and massspectrometry.

LC Method A

Instrument: Waters Acquity Ultra Performance LC

Column: ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 μm

Column Temperature: 40° C.

Mobile Phase: Solvent A: H₂O+0.05% FA; Solvent B: CH₃CN+0.05% FA

Flow Rate: 0.8 mL/min

Gradient: 0.24 min @ 15% B, 3.26 min gradient (15-85% B), then 0.5 min @85% B

Detection: UV (PDA), ELS, and MS (SQ in EI mode)

LC Method B

Instrument: Shimadzu LC-2010A HT

Column: Athena, C18-WP, 50×4.6 mm, 5 μm

Column Temperature: 40° C.

Mobile Phase: Solvent A: H₂O/CH₃OH/FA=90/10/0.1; Solvent B:H₂O/CH₃OH/FA=10/90/0.1

Flow Rate: 3 mL/min

Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then 0.8 min @100% B

Detection: UV (220/254 nm)

LC Method C

Instrument: Agilent 1100/1200 series LC system with DAD detector

Column: Atlantis dC18 (250×4.6) mm, 5 μm

Column Temperature: Ambient

Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile

Flow Rate: 1.0 mL/min

Gradient:

Time (min) 0.0 15 20 23 30 % B 10 100 100 10 10

Detection: (210-400 nm)

LC Method D

Instrument: Shimadzu LC 20AD system with PDA detector

Column: Phenomenex Gemini NX C18 (150×4.6) mm, 5 μm

Column Temperature: Ambient

Mobile Phase A: 10 mM NH₄OAC in water, Mobile Phase B: Acetonitrile

Flow Rate: 1.0 mL/min

Gradient:

Time (min) 0.0 15 20 23 30 % B 10 100 100 10 10

Detection: (210-400 nm)

Example 1. General Route of Synthesis

A compound of the present invention can be prepared, for example, from acentral core. In one embodiment, for example, the central core Structure1 is an N-protected aminoacid where X¹ is nitrogen and PG=protectinggroup. In one embodiment, the central core is coupled to an amine togenerate an amide of Structure 2 (wherein L-B includes a C(O)N moiety).Structure 2 can then be deprotected to generate Structure 3. Structure 3is coupled to Structure 4 (A-COOH) to generate a second amide bond,forming a compound within Formula I. The chemistry is illustrated inRoute 1.

In an alternative embodiment, central core Structure 5 is reacted with aheterocyclic or heteroaryl compound to generate a compound of Structure6. In one embodiment, Structure 6 is deprotected to generate acarboxylic acid, Structure 7. In one embodiment, Structure 7 is coupledto an amine to generate a compound of Formula I. This chemistry isillustrated in Route 2.

In an alternative embodiment, Structure 8 is deprotected to generate anamine which is Structure 9. Structure 9 is then coupled to generate anamide which is Structure 6. Structure 6 is then deprotected to generatea carboxylic acid which is Structure 7. Structure 7 is then coupled toform the amide which falls within Formula I. The chemistry isillustrated in Route 3.

In an alternate embodiment, a heteroaryl compound of Structure 10 iscoupled to an activated ester, Structure 11, to generate Structure 12.The ester is hydrolyzed to form acid Structure 13. Structure 13 iscoupled to Structure 3 from Route 1 to generate Structure 14. Structure14 is treated with a base such as, but not limited to, lithium hydroxideto generate Structure 15. This chemistry is illustrated in Route 4.

In another embodiment, Structure 15 is treated with diphenylphosphorylazide (DPPA) to generate the isocyanate, Structure 16. Structure 16 isthen treated with an amine or alcohol to generate ureas and carbamatescompounds of Formula I, wherein the R¹² substituent is NR⁹C(O)NR⁹R¹⁰,NR⁹C(O)NR¹⁰R²³, NR⁹C(O)NR²⁴R²⁵, NR⁹C(O)OR¹⁰ or NR⁹C(O)OR²³. In someembodiments, R⁹ is hydrogen. Structure 15 can be coupled to amines togenerate amides of Formula I, wherein the R¹² substituent is,C(O)NR²⁴R²⁵, C(O)NR⁹R³⁷, or C(O)NR²¹SO₂R²². In some embodiments, R⁹ ishydrogen. The chemistry is illustrated in Route 5.

In an alternate embodiment, a heteroaryl compound of Structure 17 iscoupled to an activated ester to generate Structure 18. The ester ishydrolyzed to form acid Structure 19. Structure 19 is coupled toStructure 3 from Route 1 to generate Structure 20. Structure 20 istreated with a base such as, but not limited to, lithium hydroxide togenerate Structure 21. This chemistry is illustrated in Route 6.

In one embodiment, Structure 21 from Route 6, is treated with, forexample, diphenylphosphoryl azide (DPPA) to generate an isocyanate,Structure 22. Structure 22 is then treated with an amine or alcohol togenerate urea and carbamate compounds within Formula I, wherein the R¹³substituent is NR⁹C(O)NR⁹R¹⁰, NR⁹C(O)NR¹⁰R²³, NR⁹C(O)R²⁴R²⁵, NR⁹C(O)OR¹⁰and NR⁹C(O)OR²³. In some embodiments, R⁹ is hydrogen. Structure 21 canbe coupled to amines to generate amides within Formula I, wherein theR¹³ substituent is C(O)NR²⁴R²⁵, C(O)NR⁹R³⁷, or C(O)NR²¹SO₂R²². In someembodiments, R⁹ is hydrogen. The chemistry is illustrated in Route 7.

In an alternate embodiment, a heteroaryl or aryl moiety is coupled to acentral core to generate 8-2. The protected acid, 8-2 is deblocked toform the carboxylic acid, 8-3. The carboxylic acid is coupled to form anamide bond (L-B) and 8-4. The heteroaryl or aryl moiety, A′, can then befurther derivitized to add substituents at the X¹¹, X¹², X¹³ and X¹⁴positions to generate compounds within Formula I. This chemistry isillustrated in Route 8.

In an alternate embodiment, Structure 9-1 is coupled to an acid,Structure 9-2, to generate Structure 9-3. The carboxylic acid, Structure9-3, is deblocked to generate carboxylic acid, Structure 9-4. Carboxylicacid Structure 9-4 is coupled to an amine to form an amide bond (L-B)and compounds within Formula I. This chemistry is illustrated in Route9.

In an alternate embodiment, a heteroaryl compound of Structure 10-1 istreated with a carboxylic acid to generate Structure 10-2. Theheteroaryl Structure 10-2 can be treated with an acylating agent togenerate Structure 10-3. In an alternate embodiment, Structure 10-2 istreated with coupling conditions to generate R⁶═CN. The nitrile can betreated with an oxime to generate an amide at the R⁶ position. Structure10-3 is treated with an activated ester to generate Structure 10-4. Insome embodiments, the leaving group, LG, is a halide. Structure 10-4 istreated with a base to generate the acid, Structure 10-5. Structure 10-5can be coupled to Structure 3 from Route 1 to generate compounds withinFormula I. This chemistry is illustrated in Route 10.

In an alternate embodiment, a heteroaryl compound of Structure 11-1 istreated with a carboxylic acid to generate Structure 11-2. Theheteroaryl Structure 11-2 can be treated with an acylating agent togenerate Structure 11-3. In an alternate embodiment, Structure 11-2 istreated with coupling conditions to generate R⁶═CN. The nitrile can betreated with an oxime to generate an amide at the R⁶ position. Structure11-3 is treated with an activated ester to generate Structure 11-4. Insome embodiments, the leaving group, LG, is a halide. Structure 11-4 istreated with a base to generate the acid, Structure 11-5. Structure 11-5is coupled to Structure 3 from Route 1 to generate compounds withinFormula I. The chemistry is illustrated in Route 11.

In an alternate embodiment, a heteroaryl compound of Structure 12-1 istreated with a carboxylic acid to generate Structure 12-2. Theheteroaryl Structure 12-2 can be treated with an acylating agent togenerate Structure 12-3. In an alternate embodiment, Structure 12-2 istreated with coupling conditions to generate R⁶═CN. The nitrile can betreated with an oxime to generate an amide at the R⁶ position. Structure12-3 is treated with an activated ester to generate Structure 12-4. Insome embodiments, the leaving group, LG, is a halide. Structure 12-4 istreated with a base to generate the acid, Structure 12-5. Structure 12-5can be coupled to Structure 3 from Route 1 to generate compounds withinFormula I. This chemistry is illustrated in Route 12.

In an alternate embodiment, a heteroaryl compound of Structure 13-1 istreated with a carboxylic acid to generate Structure 13-2. Theheteroaryl Structure 13-2 can be treated with an acylating agent togenerate Structure 13-3. In an alternate embodiment, Structure 13-2 istreated with coupling conditions to generate R⁶═CN. The nitrile can betreated with an oxime to generate an amide at the R⁶ position. Structure13-3 is treated with an activated ester to generate Structure 13-4. Insome embodiments, the leaving group, LG, is a halide. Structure 13-4 istreated with a base to generate the acid, Structure 13-5. Structure 13-5can be coupled to Structure 3 from Route 1 to generate compounds withinFormula I. The chemistry is illustrated in Route 13.

In an alternate embodiment, Structure 14-1 is coupled to an amine togenerate an amide bond (L-B), and Structure 14-2. Structure 14-2, iscoupled to an amine to generate compounds within Formula I. Thischemistry is illustrated in Route 14.

Example 2. Examples of Central Synthons

Z^(A) is halogen.

In one embodiment, deuterated L-proline synthons are disclosed.Deuterated synthons include, but are not limited to, for example, thefollowing compounds:

Structure A can be treated with deuterium oxide to generate Structure B.See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655;Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO2014/037480 (p. 103). Structure B can be reduced to generate StructureC. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655;Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. StructureC can be treated with Mitsunobu reaction conditions to generateStructure D. Structure B can be treated with DAST to generate StructureE. See, WO 2014/037480. Structure A can be treated with sodiumborodeuteride to generate Structure F. See, Dormoy, J.-R.; Castro, B.Synthesis 1986, 81-82. Compound F can be used to generate Structure K.See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Structure B can betreated with a deuterated reducing agent, for example sodiumborodeuteride to generate Structure G. Structure G can be treated withDAST to generate Structure H. Structure F can be used to generateStructure K. See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82.Structure G can be used to generate Structure I. Structure J can beprepared according to Hruby, V. J. et al. J. Am. Chem. Soc. 1979, 101,202-212. Structures A-J can be used to prepare compounds of Formula I.

Example 3. Preparation of Central-L-B Synthons

In Route 1a, 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid,5-(1,1-dimethylethyl) ester, (4S)-, CAS 209269-08-9, can be prepared asdescribed in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8,1139-1144. In Step 2, the protected azaspiro[2.4]heptane is coupled toan amine in the presence of an organic solvent, a base and a couplingreagent to generate an amide bond; the L-B moiety. In one embodiment,the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment,the organic solvent is DMF. In one embodiment, the base isdiisopropylethylamine. In one embodiment, the coupling reagent is HATU.In Step 3, the protecting group is removed. In one embodiment, thestarting material is reacted with an acid in the presence of an organicsolvent. In one embodiment, the acid is 4N hydrochloric acid. In oneembodiment, the organic solvent is dioxane.

In Route 1b, (4S) 4-oxazolidinecarboxylic acid, hydrochloride is treatedwith an amine protecting reagent. In one embodiment, the amineprotecting reagent is di-tert-butyl dicarbonate. In another embodiment,3,4-oxazolidinedicarboxylic acid, 3-(1,1-dimethylethyl) ester, (4S)-, iscommercially available from JPM2 Pharmaceuticals. In one embodiment thereaction is carried out in an organic solvent in the presence of a base.In one embodiment, the organic solvent is acetonitrile. In oneembodiment, the base is 4-dimentylaminopyridine (DMAP). In Step 2, theprotected 4-oxazolidinecarboxylic acid is coupled to an amine in thepresence of an organic solvent, a base and a coupling reagent togenerate an amide bond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 3, the protectinggroup is removed. In one embodiment, the starting material is reactedwith an acid in the presence of an organic solvent. In one embodiment,the acid is 4N hydrochloric acid. In one embodiment, the organic solventis dioxane.

In Route 1c,(S)-5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-6-caboxylic acid, CAS1129634-44-1, is commercially available from Ark Pharm. In Step 2, thecarboxylic acid is coupled to an amine in the presence of an organicsolvent, a base and a coupling reagent to generate an amide bond; theL-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the base is diisopropylethylamine. In one embodiment, thecoupling reagent is HATU. In Step 3, the protecting group is removed. Inone embodiment, the starting material is reacted with an acid in thepresence of an organic solvent. In one embodiment, the acid is 4Nhydrochloric acid. In one embodiment, the organic solvent is dioxane.

In Route 2a, commercially available Boc-L-proline is coupled to an aminein the presence of an organic solvent, a base and a coupling reagent togenerate an amide bond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 2, the Bocprotecting group is removed. In one embodiment, the starting material isreacted with an acid in the presence of an organic solvent. In oneembodiment, the acid is 4N hydrochloric acid. In one embodiment, theorganic solvent is dioxane.

In Route 2b, commercially available(1R,3S,5R)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, from Enamine, is coupled to an amine in the presence of an organicsolvent, a base and a coupling reagent to generate an amide bond; theL-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the base is diisopropylethylamine. In one embodiment, thecoupling reagent is HATU. In Step 2, the Boc protecting group isremoved. In one embodiment, the starting material is reacted with anacid in the presence of an organic solvent. In one embodiment, the acidis 4N hydrochloric acid. In one embodiment, the organic solvent isdioxane.

In Route 2c, commercially available(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid,from Manchester Organics, is coupled to an amine in the presence of anorganic solvent, a base and a coupling reagent to generate an amidebond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 2, the Bocprotecting group is removed. In one embodiment, the starting material isreacted with an acid in the presence of an organic solvent. In oneembodiment, the acid is 4N hydrochloric acid. In one embodiment, theorganic solvent is dioxane.

In Route 2d, commercially available(S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid, from Chem-Impex,is coupled to an amine in the presence of an organic solvent, a base anda coupling reagent to generate an amide bond; the L-B moiety. In oneembodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In oneembodiment, the organic solvent is DMF. In one embodiment, the base isdiisopropylethylamine. In one embodiment, the coupling reagent is HATU.In Step 2, the Boc protecting group is removed. In one embodiment, thestarting material is reacted with an acid in the presence of an organicsolvent. In one embodiment, the acid is 4N hydrochloric acid. In oneembodiment, the organic solvent is dioxane. This chemistry isillustrated in Scheme 2.

Additional starting materials that can readily be converted toCentral-L-B-Synthons include, but are not limited to:(S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid,CAS 90104-21-5, available from Ark Pharm;cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from ArkPharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid,1-(1,1-dimethylethyl) 2-ethyl ester, CAS 553650-00-3, commerciallyavailable from FCH Group; Boc-L-octahydroindole-2-carboxylic acid can bepurchased from Chem Impex. The compound,

can be prepared according to the procedures disclosed in WO 2004/111041;(S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the AldrichChemical Co.;(1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]hexane-2-carboxylicacid is available from Ark Pharm; (S)-3-Boc-thiazolidine-2-carboxylicacid is available from Alfa Aesar;(2S,4R)-1-(tert-butoxycarbonyl)-4-chloropyrrolidine-2-carboxylic acid isavailable from Arch Bioscience;(1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylicacid is available from Ark Pharm; 1,2-pyrrolidinedicarboxylic acid,3-[[(phenylmethoxy)carbonyl]amino]-, 1-(1,1-dimethylethyl) ester,(2S,3R) can be prepared as disclosed in WO 2004/007501. The Cbz groupcan be removed and the amino group can be alkylated to generate centralcore compounds of the present invention.

The compound

can be prepared as disclosed by Braun, J. V.; Heymons, Albrecht Berichteder Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930)63B, 502-7.

The compounds (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester and(2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester can be prepared as a mixture according to WO2012/093101 to Novartis and the regioisomers can be ultimately separatedonce coupled to generate the central core-L-B synthons. The compound(S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the AldrichChemical Co.

Example 4. Preparation of A-C(O)-Moiety

Examples of the preparation of the A-C(O)-Moiety can be found in Example1 and below.

In an alternate embodiment, a heteroaryl compound of Structure 1 isacylated to generate a compound of Structure 2. Structure 2 is coupledto an activated ester of Structure 3 to generate Structure 4. The esteris hydrolyzed to form acid Structure 5. This chemistry is illustrated inScheme 4a.

In an alternate embodiment, a heteroaryl compound, Structure 2-1, istreated with a halogen to generate Structure 2-2. In some embodiments,the halogen is iodine. Structure 2-2 is treated with an activated esterto generate Structure 2-3. The halide is treated with zinc cyanide togenerate nitrile, Structure 2-4. The nitrile, Structure 2-4 is treatedwith an oxime to generate the amide Structure 2-5. The ester is treatedwith an acid to generate acid, Structure 2-6. This chemistry isillustrated in Scheme 4b.

Example 5. Coupling of Central-L-B-Synthons to A-C(O)-Moieties

Examples of the coupling of central-L-B-synthons to A-C(O)-moieties canbe found in Example 1.

In an alternate embodiment, Structure 5, from Example 4 Scheme 4a, iscoupled to Structure 3 from Route 1 to generate Structure 6. Structure 6is treated with a base such as, but not limited to, lithium hydroxide togenerate Structure 7. This chemistry is illustrated in Scheme 5a.

In one embodiment, Structure 2-6 from Example 4b, is coupled to acentral core-L-B to generate Structure 2-7. Structure 2-7 is treatedwith a base to generate a carboxylic acid, Structure 2-8. In oneembodiment, the base is lithium hydroxide. This chemistry is illustratedin

Example 6. Synthesis of Amides, Carbamates, and Ureas Within Formula I

Examples of the synthesis of amides, carbamates and ureas within FormulaI can be found in Example 1 and below.

In one embodiment, Structure 1 is treated with, for example,diphenylphosphoryl azide (DPPA) to generate an isocyanate, Structure 2.Structure 2 is then treated with an amine or alcohol to generate ureaand carbamate compounds within Formula I, wherein the R¹³ substituent isNR⁹C(O)NR⁹R¹⁰, NR⁹C(O)NR¹⁰R²³, NR⁹C(O)R²⁴R²⁵, NR⁹C(O)OR¹⁰ andNR⁹C(O)OR²³. In some embodiments, R⁹ is hydrogen. Structure 1 can becoupled to amines to generate amides within Formula I, wherein the R¹³substituent is C(O)NR²⁴R²⁵, C(O)NR⁹R³⁷, or C(O)NR²¹SO₂R²². In someembodiments, R⁹ is hydrogen. The chemistry is illustrated in Scheme 6a.

Example 7. Synthesis of Intermediates 7A. (2S,4R)-Tert-Butyl2-((3-Chloro-2-Fluorobenzyl)Carbamoyl)-4-Fluoropyrrolidine-1-Carboxylate(65)

(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(2.33 g, 10 mmol) was dissolved in DMF (50 ml) and ^(i)Pr₂NEt (8.6 ml, 5eq.) was added followed by the addition of (3-chloro-2-fluorophenyl)methanamine (3.18 g 20 mmol) at 5° C. Then HATU (8 g, 2.1 eq) was addedslowly at the same temperature. The reaction mixture was then stirredfor 18 h at RT. After the completion of the reaction, monitored by HPLC,the reaction mixture was diluted with 1M citric acid solution (200ml+NaCl solid 20 g) and extracted with DCM (150 mL×2). The organic layerwas then washed with an aqueous solution of NaHCO₃ (100 ml), washed withwater (100 ml), brine (100 ml), dried over Na₂SO₄ and concentrated underreduced pressure. The remaining residue was purified by columnchromatography (eluted with DCM/EtOAc) to afford compound (63) and(2S,4R)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(65).

7B.(2S,4R)—N-(3-Chloro-2-Fluorobenzyl)-4-Fluoropyrrolidine-2-CarboxamideHydrochloride (66)

(2S,4R)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate65 (500 mg) was taken in 4N HCl dioxane (30 ml) and resulting reactionmixture was stirred at rt for 3 h. After completion of the reaction,monitored by HPLC, the solvent was removed under reduced pressure. Theresidue, 66, was used directly in the next step.

7C. 2-(3-Acetyl-1H-Indol-1-Yl)Acetic Acid (69)

A mixture of 3-acetylindole (67) (10.09 g) and t-butylbromoacetate(13.71 g) was heated at reflux in acetonitrile in the presence ofpotassium carbonate (9.7 g) for 24 h. The reaction mixture was cooled toroom temperature, filtered and evaporated to dryness. The residue waspurified by chromatography over silica gel and eluted with a mixture ofethyl acetate in methylene chloride to afford tert-butyl2-(3-acetyl-1H-indol-1-yl)acetate (68).

Tert-butyl 2-(3-acetyl-1H-indol-1-yl)acetate (68) was stirred overnightin a mixture of trifluoroacetic acid amd methylene chloride, dilutedwith methanol and evaporated to dryness. The residue was treated with 1Msodium hydroxide and extracted with methylene chloride. The aqueouslayer was acidified with 6M HCl and the residue filtered, washed withwater and dried to afford 2-(3-acetyl-1H-indol-1-yl)acetic acid (69).

7D. 1-(3-Amino-1H-Indol-1-Yl)Ethanone Hydrochloride (74)

To a stirred solution of AgNO₃ (9.3 g, 1.07 equiv) in acetonitrile wasadded benzoyl chloride (7.47 g, 1.04 equiv) dropwise at 0° C. Themixture was stirred for 10 min, and a solution of 1H-indole (6 g, 1equiv) in acetonitrile was added at 0° C. and stirred for 1 h at RT. Thereaction mixture was poured into ice to afford a dark brown precipitate.The precipitate was filtered, washed with water and dried. The cruderesidue was purified by flash column chromatography (ISCO withhexanes/EtOAc) to afford 3-nitro-1H-indole (71).

A stirred solution of 3-nitro-1H-indole (1 g, 1 equiv) in dry THF wascooled to 5° C. Then tBuOK (830 mg, 1.2 equiv) was added slowly and theresulting mixture was stirred 10 min. Acetyl chloride (525 mg, 1.2equiv) was added and the reaction mixture was stirred for 30 min. Aftercompletion of the reaction as monitored by HPLC, solvent was removedunder reduced pressure, diluted with DCM and washed with an aqueoussolution of NaHCO₃. The organic layer was separated, washed with brineand concentrated under reduced pressure. The remaining residue waspurified by flash column chromatography (ISCO eluted with DCM/EtOAc) toafford 1-(3-nitro-1H-indol-1-yl)ethanone (72).

To a mixture of 1-(3-nitro-1H-indol-1-yl)ethanone (600 mg, 2.942 mmol)and di-tert-butyl dicarbonate (1.925 g, 8.826 mmol) in methanol (50 mL)was added 5% Pd/C (20 mg). The resulting reaction mixture was stirredunder hydrogen for 24 h. After completion of the reaction, Pd/C wasfiltered using Celite®, and the filtrate was concentrated under reducedpressure. The remaining residue was purified by flash columnchromatography (ISCO eluted with DCM/EtOAc) to afford tert-butyl(1-acetyl-1H-indol-3-yl)carbamate (73).

Tert-butyl (1-acetyl-1H-indol-3-yl) carbamate (300 mg, 1.1 mmol) wastaken in 4N HCl dioxane (10 ml) and resulting reaction mixture wasstirred at rt for 3 h. After completion of the reaction, solvent wasremoved under reduced pressure. This material,1-(3-amino-1H-indol-1-yl)ethanone hydrochloride (74), was used directlyin the next synthetic step.

7E. 2-(3-Acetyl-6-Hydroxy-1H-Indol-1-Yl)Acetic Acid (80)

6-Benzyloxyindole was acetylated using the reported procedure (Eur. J.Med Chem., (2011), 46, 756) and alkylated following the proceduredescribe for compound 69. The benzyl group was removed by hydrogenationover palladium on charcoal and the t-butyl group removed again asdescribed for compound 69.

7F. 2-(3-Acetyl-5-Hydroxy-1H-Indol-1-Yl)Acetic Acid (85)

To a stirred solution of 5-(benzyloxy)-1H-indole (81) (11.08 g, 1 equiv)in DCM (200 mL) was added diethylaluminium chloride (1 M solution inHexane; 74.6 mL, 1.5 equiv) drop wise at 0° C. The mixture was stirredfor 30 min, and then a solution of acetyl chloride (5.3 mL, 1.5 equiv)in DCM (150 mL) was added at 0° C. and the reaction was stirred for 1 hat 0° C. A 5% aqueous citric acid solution was added at 0° C. and thereaction was stirred for 15 min at RT. The precipitate was filtered,washed with water, and the organic filtrate was dried and concentratedunder reduced pressure. The residue was purified by flash columnchromatography (silica gel eluted with DCM/CH₃OH) to afford1-(5-(benzyloxy)-1H-indol-3-yl)ethanone (82).

To a suspension of 1-(5-(benzyloxy)-1H-indol-3-yl)ethanone (6.5 g, 1equiv) and K₂CO₃ (3.72 g, 1.1 equiv) in acetonitrile (50 mL) was addedtert-butyl 2-bromoacetate (3.92 mL, 1.1 equiv) dropwise at RT. Theresulting mixture was then heated at reflux for 18 h. After cooling toRT, the mixture was diluted with DCM (100 mL) and filtered through aCelite® pad. The filtrate was concentrated under reduced pressure. Theremaining residue was purified by flash column chromatography (silicagel eluted with DCM/EtOAc) to afford tert-butyl2-(3-acetyl-5-(benzyloxy)-1H-indol-1-yl)acetate (83).

To tert-butyl 2-(3-acetyl-5-(benzyloxy)-1H-indol-1-yl)acetate (6 g) inTHF (80 mL) was added Pd/C (0.05 equiv). The reaction mixture wasstirred at RT for 5 h under H₂ (1 atm). The reaction mixture wasfiltered through a pad of Celite® and the pad was washed with CH₂Cl₂ andMeOH. The filtrate was concentrated under reduced pressure and theremaining residue was purified by flash column chromatography (silicagel eluted with DCM/EtOAc) to afford tert-butyl2-(3-acetyl-5-hydroxy-1H-indol-1-yl)acetate (84).

Tert-Butyl 2-(3-acetyl-5-hydroxy-1H-indol-1-yl)acetate (814 mg, 2.8mmol) was taken up in 4 N HCl dioxane (10 mL) and the resulting reactionmixture was stirred at RT for 48 h. The solvent was then removed underreduced pressure to afford 2-(3-acetyl-5-hydroxy-1H-indol-1-yl)aceticacid (85) which could be used directly in the next synthetic step.

7G. N-(2-((2R,4R)-4-fluoropyrrolidin-2-yl)ethyl)benzenesulfonamidehydrochloride (91)

To a solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1equiv) in THF (10 vol) at 0° C. was added borane tetrahydrofuran complex(2.1 equiv). The reaction mixture was stirred at room temperature for 2h and then cooled at 0° C. The resulting mixture was quenched withsaturated K₂CO₃ solution and extracted with ethyl acetate. The organiclayer was separated, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel using DCM/MeOH to afford the title compound (86).

To a solution of tert-butyl(2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1 equiv) inDCM (20 Vol) at 0° C. was added methanesulfonyl chloride (1.5 equiv) andtriethylamine (3 equiv). The reaction mixture was stirred at 0° C. for 1h. The resulting mixture was diluted with ethyl acetate, washed with 1NHCl and saturated NaHCO₃ solution. The organic layer was separated,dried over anhydrous Na₂SO₄, filtered and concentrated. Crude tert-butyl(2S,4R)-4-fluoro-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(87) was dissolved in DMSO (10 Vol) and sodium cyanide (3 equiv) wasadded. The reaction mixture was stirred at 50° C. for 15 h. Theresulting mixture was cooled to room temperature and quenched with waterand was extracted with ethyl acetate. The organic layer was separated,dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel using Hexane/EtOAc toafford tert-butyl(2R,4R)-2-(cyanomethyl)-4-fluoropyrrolidine-1-carboxylate (88).

To a solution of tert-butyl(2R,4R)-2-(cyanomethyl)-4-fluoropyrrolidine-1-carboxylate (88) (1 equiv)in methanol (5 Vol) was added Raney Ni (1.2 equiv) and triethylamine (2equiv). The reaction mixture was stirred at room temperature at 3.5millibar pressure under hydrogen atmosphere for 16 h. The resultingmixture was filtered and concentrated. The residue was purified bycolumn chromatography on silica gel using DCM/MeOH to afford tert-butyl(2R,4R)-2-(2-aminoethyl)-4-fluoropyrrolidine-1-carboxylate (89).

To a solution of tert-butyl(2R,4R)-2-(2-aminoethyl)-4-fluoropyrrolidine-1-carboxylate (89) (1equiv) in THF (10 vol) at 0° C. under nitrogen atmosphere was addedbenzenesulfonyl chloride (1.5 equiv) and triethylamine (3 equiv). Thereaction mixture was stirred at room temperature for 16 h and thenconcentrated. The residue was purified by column chromatography onsilica gel using Hexane/EtOAc to afford tert-butyl(2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidine-1-carboxylate(90).

To a solution of tert-butyl(2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidine-1-carboxylate(1 equiv) in 1,4-dioxane (2 vol) at 0° C. was added 4 N HCl in dioxane(10 vol). The reaction mixture was stirred at room temperature for 4 hand then concentrated. The residue was taken up in MTBE and stirred for30 min. The resultant solid was filtered and dried to afford 91.

Example 8. Synthesis of(2S,4R)—N2-(1-Acetyl-1H-Indol-3-Yl)-N1-(3-Chloro-2-Fluorobenzyl)-4-Fluoropyrrolidine-1,2-Dicarboxamide(97)

To a stirred solution of methyl 1H-indole-5-carboxylate (92) (10 g, 1equiv) in DCM (200 mL) was added diethylaluminium chloride (1 M solutionin hexane; 85.71 mL, 1.5 equiv) dropwise at 0° C. The mixture wasstirred for 30 min and then a solution of acetyl chloride (6 mL, 1.5equiv) in DCM (150 mL) was added at 0° C. and stirred for 1 h at 0° C. A5% aqueous citric acid solution was added at 0° C. and the reactionmixture was stirred for 15 min at RT. The precipitate was collected byfiltration, washed with water, and dried. The residue was purified byflash column chromatography (silica gel eluted with DCM/CH₃OH) to affordmethyl 3-acetyl-1H-indole-5-carboxylate (93).

To a suspension of methyl 3-acetyl-1H-indole-5-carboxylate (93) (6 g, 1equiv) and K₂CO₃ (4.19 g, 1.1 equiv) in 50 mL acetonitrile was addedtert-butyl 2-bromoacetate (4.42 mL, 1.1 equiv) dropwise at RT. Theresulting mixture was then heated at reflux for 18 h. After cooling toRT, the mixture was diluted with DCM (100 mL), filtered through a pad ofCelite® and the filtrate was concentrated under reduced pressure. Theremaining residue was purified by flash column chromatography (silicagel eluted with DCM/EtOAc) to afford Methyl3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-indole-5-carboxylate (94).

Methyl 3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-indole-5-carboxylate(3 g, 9.06 mmol) was taken up in 4 N HCl dioxane (50 mL) and theresulting reaction mixture was stirred at RT for 48 h. The solvent wasthen removed under reduced pressure and the remaining material2-(3-acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (95) was useddirectly in the next synthetic step.

2-(3-Acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (95) (2 g, 1equiv) was dissolved in DMF (50 mL) and ^(i)Pr₂NEt (3.95 mL, 5 equiv)was added, followed by the sequential addition of(2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride 66 (2.254 g, 1 equiv) and HATU (5.8 g, 2.1 equiv) slowlyat 5° C. The reaction mixture was then stirred for 18 h at RT, dilutedwith 1 M citric acid solution (100 mL, containing 10 g NaCl), andextracted with DCM (50 mL×2). The organic layer was washed with anaqueous solution of NaHCO₃ (40 mL), washed with water (40 mL), brine (40mL), dried over Na₂SO₄, and concentrated under reduced pressure. Theremaining residue was purified by flash column chromatography (silicagel eluted with DCM/CH₃OH) to afford methyl3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(96).

Methyl3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(96) (3.86 g, 1 equiv) was taken up in a mixture of THF (20 mL) andmethanol (20 mL), and then LiOH (1.832 g, 6 equiv) in water (20 mL) wasadded. The resulting reaction mixture was stirred at RT for 48 h. Thesolvent was removed under reduced pressure and water (30 mL) was added.Acidification with 4 N HCl produced a white precipitate that wascollected by filtration and dried in vacuo. This material3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (97) was used directly in the next synthetic step.

Example 9. Synthesis of Cyclopropyl(3-Acetyl-1-(2-((2S,4R)-2-((3-Chloro-2-Fluorobenzyl)Carbamoyl)-4-Fluoropyrrolidin-1-Yl)-2-Oxoethyl)-1H-Indol-5-Yl)Carbamate(Compound 14)

To a suspension of3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (97) (155 mg, 0.3 mmol, 1 equiv) in THF (20 mL) was added Et₃N (38μL, 1 equiv) and the resulting solution was stirred at RT under anitrogen atmosphere for 15 min. DPPA (64 μL, 1 equiv) was added and thereaction was further stirred at RT under nitrogen for 18 h. The reactionmixture was concentrated under reduced pressure and the residue acylazide intermediate was suspended in a mixture of toluene (20 mL) and THF(5 mL). This mixture was refluxed under nitrogen for 4 h and evaporatedto dryness under reduce pressure. The remaining crude isocyanate(2S,4R)-1-(2-(3-acetyl-5-isocyanato-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(98) was used directly in the next step.

Compound 98 was dissolved in a mixture of THF (7 mL), ACN (3 mL), andcyclopropanol (35 mg, 2 equiv), followed by the addition of NEt₃ (76 μL,2 equiv) at 0° C. The reaction mixture was then stirred for 24 h at RT.The reaction mixture was concentrated under reduced pressure and theremaining residue was purified by flash column chromatography (silicagel eluted with DCM/CH₃OH) to afford the product cyclopropyl(3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)carbamate(14).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 0.68-0.72 (m, 4H),2.00-2.17 (m, 1H), 2.40 (s, 3H), 2.49-2.56 (m, 1H), 3.89 (ddd, J=22.8,9.6, 2.8 Hz, 1H), 4.05-4.14 (m, 1H), 4.32 (dd, J=20.8, 6.0 Hz, 1H),4.42-4.49 (m, 2H), 5.12 (d, J=17.2 Hz, 1H), 5.33 (d, J=17.2 Hz, 1H),5.50 (d, J=52.8 Hz, 1H), 6.97-7.01 (m, 1H), 7.15-7.45 (m, 4H), 8.18 (s,1H), 8.31 (s, 1H), 8.59 (t, J=5.6 Hz, 1H), 9.49 (s, 1H). ¹⁹F NMR (376MHz, DMSO-d₆): (major rotamer) δ−121.8, −176.1. LC (method 1):t_(R)=1.78 min. LC/MS (EI) m/z: [M+H]⁺ calcd for C₂₈H₂₇ClF₂N₄O₅, 573;found, 573.

Example 10. Synthesis ofN-(3-Acetyl-1-(2-((2S,4R)-2-((3-Chloro-2-Fluorobenzyl)Carbamoyl)-4-Fluoropyrrolidin-1-Yl)-2-Oxoethyl)-1H-Indol-5-Yl)-3,3-Difluoropiperidine-1-Carboxamide(Compound 16)

Compound 98 was dissolved in a mixture of THF (7 mL), ACN (3 mL), and3,3-difluoropiperidine hydrochloride (51.81 mg, 1.1 equiv), followed bythe addition of NEt₃ (76 μL, 2 equiv) at 0° C. The reaction mixture wasthen stirred for 24 h at RT. The reaction mixture was concentrated underreduced pressure and the remaining residue was purified by flash columnchromatography (silica gel eluted with DCM/CH₃OH) to affordN-(3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(16).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.69-1.76 (m, 2H),2.01-2.17 (m 3H), 2.41 (s, 3H), 3.52 (t, J=5.2 Hz, 1H), 3.78-3.95 (m,3H), 4.13 (dd, J=9.2, 12.4 Hz, 1H), 4.32 (dd, J=20.4, 6.0 Hz, 1H),4.42-4.49 (m, 2H), 5.12 (d, J=17.2 Hz, 1H), 5.33 (d, J=17.2 Hz, 1H),5.50 (d, J=52.8 Hz, 1H), 6.99-7.03 (m, 1H), 7.22-7.25 (m, 1H), 7.29-7.48(m, 3H), 8.16 (s, 1H), 8.19 (d, J=2 Hz, 1H), 8.59 (t, J=6 Hz, 1H), 8.62(s, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆): (major rotamer) δ −101.06, −121.25,−176.1. LC (method 1): t_(R)=1.82 min. LC/MS (EI) m/z: [M+H]⁺ calcd forC₃₀H₃₀ClF₄N₅O₄, 636; found, 636.

Example 11. Synthesis of3-Acetyl-1-(2-((2S,4R)-2-((3-Chloro-2-Fluorobenzyl)Carbamoyl)-4-Fluoropyrrolidin-1-Yl)-2-Oxoethyl)-N-Cyclopropylsulfonyl)-1H-Indole-6-Carboxamide(Compound 48)

Methyl 3-acetyl-1H-indole-6-carboxylate (99) was prepared according tothe procedure published by MacKay et al. (MacKay, J. A.; Bishop, R.;Rawal, V. H. Org. Lett. 2005, 7, 3421-3424.)

A mixture of 150 mg (0.68 mmol) of methyl3-acetyl-1H-indole-6-carboxylate, (0.12 mL (0.76 mmol) of tert-butylbromoacetate, and 249 mg (0.76 mmol) cesium carbonate in anhydrousacetonitrile (15 mL) was heated at reflux for 18 h. The reaction mixturewas then cooled to RT and the solvent was removed under reducedpressure. The residue was taken up in a 2:1 mixture of EtOAc and water(30 mL: 15 mL). The two layers were separated and the organic layer waswashed with brine (2×15 mL). Finally, the organic layer was dried(Na₂SO₄) and concentrated to obtain 283 mg of the product methyl3-acetyl-1-(2-tert-butoxy)-2-oxoethyl)-1H-indole-6-carboxylate (100) asa yellow solid.

100 mg of methyl3-acetyl-1-(2-tert-butoxy)-2-oxoethyl)-1H-indole-6-carboxylate (0.3mmol) was stirred in 4 N HCl in dioxane (15 mL) at RT for 18 h. Thevolatiles were removed under reduced pressure. The residue was dissolvedin 5 mL of DMF. To this solution was added 140 mg (0.36 mmol) of the TFAsalt of 66, followed by 0.26 mL of N,N-diisopropylethylamine (1.5 mmol).HATU (137 mg, 0.36 mmol) was added and the reaction mixture was stirredovernight at RT. The reaction mixture was diluted with EtOAc (20 mL) andwater (15 mL). The organic layer was separated, washed with brine (3×15mL), dried (Na₂SO₄), concentrated in vacuo, and the residue was purifiedby column chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) to afford128 mg ofmethyl-3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylate(103) as a yellow solid.

A mixture of 128 mg (0.24 mmol) ofmethyl-3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylatein THF (5 mL) and 1 N LiOH (10 mL) was stirred at RT for 18 h. Thesolvent (THF) was removed under reduced pressure and the remaining waterlayer was washed with EtOAc (5 mL), acidified with 2 N HCl, andextracted with EtOAc (20 mL). The organic layer was washed with water,dried, and concentrated to obtain 126 mg of the product3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylicacid (104) as a yellow solid.

To a stirred solution of 177 mg (0.34 mmol) of3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl-1H-indole-6-carboxylicacid in DMF (8 mL) was added 207 mg (1.71 mmol) ofcyclopropanesulfonamide, 390 mg (1.03 mmol) of HATU, and 0.4 mL (2.4mmol) DIEA. The reaction mixture was heated at 60° C. for 36 h. Thereaction mixture was cooled to RT and the solvent was removed underreduced pressure. The residue was purified by preparative HPLC to afford63 mg of the desired product3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-cyclopropylsulfonyl)-1H-indole-6-carboxamide(48) as a white solid.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.12 (m, 4H), 2.11 (m, 1H),2.48 (s, 3H), 3.15 (m, 1H), 3.92 (m, 1H), 4.16 (m, 2H), 4.32 (m, 2H),4.49 (m, 2H), 5.48 (m, 2H), 6.92 (t, 1H), 7.21 (t, 1H), 7.43 (t, 1H),7.81 (d, 1H), 8.30 (d, 1H), 8.44 (s, 1H), 8.65 (t, 1H). ³¹F NMR (376MHz, DMSO-d₆): (major rotamer) δ −121.6, −176.0. LC (method 1):t_(R)=1.52 min. LC/MS (EI) m/z: [M+H]⁺ calcd for C₂₈H₂₇ClF₂N₄O₆S,621.05; found, 621.00.

Example 12. Additional Examples of Compounds2-(3-Carbamoyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (110)

To a solution of methyl 1H-indazole-5-carboxylate (105) (10 g, 1 eq.) inTHF (100 mL) was added iodine (21.6 g, 1.5 eq.) and potassiumtert-butoxide (16 g, 2.5 eq.) at 0° C. The reaction mixture was stirredat room temperature for 2 h. The mixture was diluted with 10% sodiumthiosulfate in water and extracted twice with EtOAc. The combinedorganic extracts were washed with brine and evaporated to dryness. Theresultant solid was slurried with MTBE, filtered and dried to afford 106(13 g).

To a mixture of methyl 3-iodo-1H-indazole-5-carboxylate (106) (30 g, 1eq.) and potassium carbonate (34.3 g, 2.5 eq.) in DMF (300 mL) was addedtert-butyl bromoacetate (17.6 mL, 1.2 eq.) drop wise at roomtemperature. The resulting mixture was stirred at 50° C. for 3 h. Thereaction mixture was poured into water and extracted with EtOAc (2×100mL). The combined organic extracts were concentrated under vacuum. Thematerial thus obtained was used without further purification in the nextstep.

A mixture of methyl1-(2-(tert-butoxy)-2-oxoethyl)-3-iodo-1H-indazole-5-carboxylate (107)(40 g, 1 eq.), Zn(CN)₂ (13.5 g, 1.2 eq.), Pd(dppf)Cl₂ (7.9 g, 0.1 eq.),Pd₂(dba)₃ (8.8 g, 0.1 eq.), water (80 mL) and DMF (400 mL) was stirredat 80° C. for 5 h under nitrogen. The reaction mixture was diluted withEtOAc and then successively washed with water, sat. aquoeous NaHCO₃ andbrine. The organic layer was concentrated under vacuum. The residue waspurified by column chromatography over silica gel (eluent: Hexane/EtOAc)to afford the compound 108.

A mixture of methyl1-(2-(tert-butoxy)-2-oxoethyl)-3-cyano-1H-indazole-5-carboxylate (108)(20 g, 1 eq.), acetaldoxime (7.5 g, 2 eq.), Pd(OAc)₂ (0.7 g, 0.05 eq.)and PPh₃ (1.7 g, 0.1 eq.) in aqueous ethanol (500 mL, H₂O/EtOH (100mL/400 mL) was heated at reflux for 3 h under a nitrogen atmosphere. Thereaction mixture was filtered through Celite® and the solvent wasremoved under vacuum. The crude residue was purified by columnchromatography over silica gel (eluent: Hexane/EtOAc) to afford compound109.

Methyl1-(2-(tert-butoxy)-2-oxoethyl)-3-carbamoyl-1H-indazole-5-carboxylate (3g, 9.06 mmol) was taken up in 4N HCl in dioxane (50 mL) and resultingreaction mixture was stirred at RT for 48 h. After completion of thereaction, the solvent was removed under reduced pressure to affordcompound 110.

(2S,4R)—N-(2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (115)

A mixture of 4-bromo-5-fluoroaniline (111) (30 g), 2-chlorophenylboronicacid (112) (60 g), K₂CO₃ (91 g) and Pd(dppf)₂Cl₂ (19.25 g) in aq.dioxane (dioxane 400 mL, H₂O 100 mL) was purged with argon in a pressurevessel for 5 min and stirred for 15 h at 100° C. The solvent was removedunder reduced pressure and the residue was purified by flash columnchromatography over silica gel. The purified material was then dissolvedin MeOH and treated with HCl/MeOH. The solvent was removed and the solidwas washed with IPA-heptane (1/1) to afford compound 113.

To an ice-cold solution of N-Boc-4-fluoroproline (63) (530 mg) in DCM(20 mL), was added 1-chloro-N,N,2-trimethyl-1-propenylamine (0.333 mL,1.1 eq.) dropwise with stirring. Stirring was continued for 3 h at thistemperature, then compound 113 (640 mg, 1.1 eq.) was added, followed by1.12 mL of DIEA (3 eq.). The cooling bath was removed and the reactionmixture stirred overnight at RT. After completion of the reaction, thereaction mixture was added to water (20 mL) and extracted with DCM (2×25mL). The organic layer was washed successively with aqueous NaHCO₃ (20mL), water (20 mL), and brine (20 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel (ISCO eluent: Hexanes/EtOAC) toafford compound 114.

(2S,4R)-tert-Butyl2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (114) (700 mg) was taken up in 4N HCl indioxane (25 mL) and the resulting reaction mixture was stirred at RT for3 h. After completion of the reaction, the solvent was removed underreduced pressure. The residue, compound 115 was used without furtherpurification.

(1R,3S,5R)—N-(3-Chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (118)

To an ice-cold solution of(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (116) (516 mg) in 20 mL of DCM was added1-chloro-N,N,2-trimethyl-1-propenylamine (0.333 mL, 1.1 eq.) dropwisewith stirring. The stirring was continued for 3 h at this temperature,then compound 113 (640 mg, 1.1 eq.) was added, followed by 1.12 mL ofDIEA (3 eq.). The cooling bath was removed and the reaction mixture wasstirred overnight at RT. The reaction mixture was added to water (20 mL)and extracted with DCM (2×25 mL). The organic layer was washedsuccessively with an aqueous solution of NaHCO₃ (20 mL), water (20 mL),brine (20 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash column chromatography oversilica gel (ISCO eluent: Hexanes/EtOAC) to afford compound 117.

(2S,4R)-tert-Butyl2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(117) (700 mg) was taken up in 4N HCl in dioxane (25 mL) and theresulting reaction mixture was stirred at RT for 3 h. After completionof the reaction, the solvent was removed under reduced pressure. Theresidue, compound 118, was used without further purification.

(1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (120)

(1R,3S,5R)-2-(Tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (116, 2.27 g, 10 mmol) was dissolved in DMF (50 mL) and DIEA (8.6mL, 5 eq.) was added followed by the addition of(3-chloro-2-fluorophenyl) methanamine (64, 3.18 g, 20 mmol) at 5° C.HATU (8 g, 2.1 eq) was added slowly at the same temperature and thereaction mixture was stirred for 18 h at RT. After completion of thereaction, the reaction mixture was diluted with 1M citric acid solution(200 mL+NaCl solid 20 g) and extracted with DCM (150 mL×2). The organiclayer was washed with an aqueous solution of NaHCO₃ (100 mL), water (100mL), brine (100 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography over silicagel (eluent: DCM/EtOAc) to afford (1R,3S,5R)-tert-butyl3-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(119).

(2S,4R)-tert-butyl (1R,3S,5R)-tert-butyl3-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(119, 500 mg) was taken up in 4N HCl in dioxane (30 mL) and resultingreaction mixture stirred at RT for 3 h. After completion of thereaction, solvent was removed under reduced pressure. The residue,compound 120, was used without any purification.

(2S,4R)—N-(3-(3-Chloropyridin-2-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (124)

A mixture of 3-bromo-2-fluoroaniline (111, 10 g),(3-chloropyridin-2-yl)boronic acid (121, 20 g), K₂CO₃ (30 g) andPd(dppf)₂Cl₂ (6.42 g) in solvent (dioxane 130 mL, H₂O 33 mL) was purgedwith argon in a pressure vessel for 5 min and stirred for 15 h at 100°C. The solvent was removed under reduced pressure and the residue waspurified by flash column chromatography over silica gel. The purifiedmaterial was then dissolved in MeOH and treated with HCl/MeOH. Thesolvent was removed and the solid was washed with IPA-heptane (1/1) toafford 3-(3-chloropyridin-2-yl)-2-fluoroaniline hydrochloride (122).

To an ice-cold solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(63, 530 mg) in 20 mL of DCM, 1-chloro-N,N-2-trimethyl-1-propenylamine(0.333 mL, 1.1 eq.) was added dropwise with stirring. The stirring wascontinued for 3 h at this temperature and then3-(3-chloropyridin-2-yl)-2-fluoroaniline hydrochloride (122) (642 mg,1.1 eq.) was added followed by 1.12 mL of DIEA (3 eq.). The cooling bathwas removed and the reaction mixture was stirred overnight at RT. Thereaction mixture was added to water (20 mL) and extracted with DCM (2×25mL). The organic layer was washed successively with an aqueous solutionof NaHCO₃ (20 mL), water (20 mL), and brine (20 mL), then dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash column chromatography over silica gel (ISCO eluted withhexanes/EtOAC) to afford (2S,4R)-tert-butyl2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate,compound 123.

(2S,4R)-Tert-butyl2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(123, 700 mg) was taken up in 4N HCl dioxane (25 mL) and the resultingreaction mixture was stirred at RT for 3 h. After completion of thereaction, the solvent was removed under reduced pressure. The residue,compound 124 was used without further purification.

(2S,4R)—N-(6-Bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (127)

To an ice-cold solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(63, 530 mg) and DCM (20 mL) was added1-chloro-N,N,2-trimethyl-1-propenylamine (0.333 mL, 1.1 eq.) dropwisewith stirring. The stirring was continued for 3 h at this temperatureand 6-bromopyridin-2-amine (125, 427 mg) was added followed by 1.12 mLof DIEA (3 eq.). The cooling bath was removed and the reaction mixturewas stirred overnight at RT. After completion of the reaction, thereaction mixture was added to water (20 mL) and extracted with DCM (2×25mL). The organic layer was washed successively with an aqueous solutionof NaHCO₃ (20 mL), water (20 mL), and brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified byflash column chromatography over silica gel (eluent Hexanes/EtOAC) toafford (2S,4R)-tert-butyl2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(126).

(2S,4R)-Tert-butyl2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(126, 700 mg) was taken up in 4N HCl dioxane (25 mL) and the resultingreaction mixture was stirred at RT for 3 h. After completion of thereaction, the solvent was removed under reduced pressure. The residue,compound 127 was used without further purification.

3-Acetyl-1-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (129)

Compound 128 was prepared from2-(3-acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (95) 275 mg)and(1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (120, 305 mg) as described in Scheme 15 and thenhydrolyzed following procedures described in Scheme 8 to afford 129.

3-Acetyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (131)

Compound 130 was prepared from2-(3-acetyl-5-(methoxycarbonyl)-1H-indol-1-yl)acetic acid (95, 275 mg)and(2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (115, 373 mg)) as described in Scheme 15 to affordcompound 130 and then hydrolyzed following procedures described inScheme 8 to afford compound 131.

3-Carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylicacid (133)

Compound 132 was prepared from2-(3-carbamoyl-5-(methoxycarbonyl)-1H-indazol-1-yl)acetic acid (110, 277mg) and(2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (65, 373 mg) as described in Scheme 15 to afford compound132 and then hydrolyzed following procedures described in Scheme 8 toafford compound 133.

3-Carbamoyl-1-(2-((1R,3S,5R)-3-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazole-5-carboxylicacid (135)

Compound 134 was prepared from2-(3-carbamoyl-5-(methoxycarbonyl)-1H-indazol-1-yl)acetic acid (110, 277mg) and(1R,3S,5R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (119, 367 mg) as described in Scheme 15 to afford compound134 and then hydrolyzed following procedures described in Scheme 8 toafford compound 135.

3-Carbamoyl-1-(2-((2S,4R)-2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylicacid (137)

Compound 136 was prepared from2-(3-carbamoyl-5-(methoxycarbonyl)-1H-indazol-1-yl)acetic acid (110, 277mg) and(2S,4R)—N-(3-(3-chloropyridin-2-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (124, 374 mg) as described in Scheme 15 to afford compound136 and then hydrolyzed following procedures described in Scheme 8 toafford 137.

1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-3-carbamoyl-1H-indazole-5-carboxylicacid (139)

Compound 138 was prepared from2-(3-carbamoyl-5-(methoxycarbonyl)-1H-indazol-1-yl)acetic acid (110, 277mg) and(2S,4R)—N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (127, 325 mg) as described in Scheme 15 to afford compound138 and then hydrolyzed following procedures described in Scheme 8 toafford 139.

(2S,4R)-1-(2-(3-acetyl-5-(3-cyclopropylureido)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(1)

To a suspension of3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (97, 517 mg, 1 mmol, 1 eq.) in THF (60 mL) was added Et₃N (127 μl,1 eq.) and the resulting solution was stirred at RT under nitrogen for15 min. DPPA (213 μl, 1 eq.) was added and the reaction was furtherstirred at RT under nitrogen for 18 h. After completion of the reaction,THF was evaporated and the residue was suspended in toluene (60 mL) andTHF (15 mL). The mixture was heated at reflux under nitrogen for 4 huntil completion of the reaction to afford crude isocyanate, 98, whichwas used directly in the next step.

Isocyanate 98 was dissolved in THF (20 mL), ACN (10 mL) andcyclopropylamine (17 mg, 2 eq.) which was followed by the addition ofEt₃N (253 μl, 2 eq.) at 0° C. The reaction mixture was then stirred for24 h at RT. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel (eluant DCM/CH₃OH) to affordcompound 1.

¹H-NMR (400 MHz, DMSO-d₆): (major rotamer) δ 0.40-0.66 (m, 4H) 2.00-2.17(m, 1H), 2.40 (s, 3H), 2.46-2.58 (m, 1H), 3.85-3.95 (m, 1H), 4.09-4.18(m, 1H), 4.15 (dd, J=21.2, 12.4 Hz, 1H), 4.25-4.49 (m, 2H), 5.06 (d,J=17.2 Hz, 1H), 5.32 (d, J=17.2 Hz, 1H), 5.50 (d, J=53.2 Hz, 1H), 6.21(s, 1H), 6.99-7.07 (m, 1H), 7.15-7.45 (m, 4H), 8.15 (s, 2H), 8.27 (s,1H), 8.59 (t, J=5.6 Hz, 1H), 10.05 (s, 1H). LC (method 1): tR=1.24 min.LC/MS (APCI) m/z: [M+H]⁺, 572

(1R,3S,5R)-2-(2-(3-acetyl-5-(3-cyclopropylureido)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(3)

3-Acetyl-1-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indole-5-carboxylic acid (129, 512 mg)was converted to the isocyanate, compound 140, and reacted withcyclopropanamine (114 mg) to afford compound 3 following proceduresdescribed in Scheme 24.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 0.42-1.07 (m, 6H) 1.88 (m,1H), 2.18-2.63 (m, 2H), 2.40 (s, 3H), 2.49-2.56 (m, 1H), 3.7 (m, 1H),4.27-4.40 (m, 3H), 5.23 (d, J=17.2 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H),6.21 (d, J=2 Hz, 1H), 7.08 (m, 1H), 7.20 (m, 1H), 7.32-7.44 (m, 3H),8.14 (s, 1H), 8.21 (s, 1H), 8.43 (s, 1H), 8.45 (m, 1H). LC (method 1):tR=1.52 min. LC/MS (APCI) m/z: [M+H]+ 566

N-(3-acetyl-1-(2-((2S,4R)-2-(2′-chloro-2-fluorobiphenyl-3-ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(18)

3-Acetyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (131, 580 mg) was converted to the isocyanate, compound 141, andthe reacted with 3,3-difluoropiperidine (242 mg) to afford compound 18following procedures described in Scheme 24.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.71 (m, 2H) 2.01-2.09 (m,2H), 2.36 (s, 3H), 2.49-2.65 (m, 1H), 3.27 (m, 1H), 3.51 (m, 2H), 3.79(m, 2H), 3.80-4.25 (m, 2H), 4.77 (m, 1H), 5.17 (d, J=17.2 Hz, 1H), 5.33(d, J=17.2 Hz, 1H), 5.50 (d, J=52.8 Hz, 1H), 7.04-7.59 (m, 8H), 8.01 (m,1H), 8.17 (s, 2H), 8.61 (s, 1H), 10.02 (s, 1H). LC (method 1): tR=2.25min. LC/MS (APCI) m/z: [M+H]+ 698.

1-(2-((2S,4R)-2-(2′-chloro-2-fluorobiphenyl-3-ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indazole-3-carboxamide(24)

3-Carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylicacid (133, 582 mg) was converted to the isocyanate compound 142 and thentreacted with 3,3-difluoropiperidine (242 mg) to afford compound 24following procedures described in Scheme 24.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.71 (m, 2H) 2.01-2.3 (m,3H), 2.60 (m, 1H), 3.52 (m, 2H), 3.79-4.40 (m, 5H), 4.77 (m, 1H),5.39-5.75 (m, 4H), 7.04-7.70 (m, 8H), 8.01 (m, 1H), 8.18 (s, 1H), 8.77(s, 1H), 10.00 (s, 1H). LC (method 1): tR=2.09 min. LC/MS (APCI) m/z:[M+H]+ 700.

1-(2-((1R,3S,5R)-3-(2′-chloro-2-fluorobiphenyl-3-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indazole-3-carboxamide(28)

3-Carbamoyl-1-(2-((1R,3S,5R)-3-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazole-5-carboxylicacid (135, 576 mg) was converted to the isocyanate 143 and then reactedwith 3,3-difluoropiperidine (242 mg) to afford compound 28 followingprocedures described in Scheme 24.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 0.74-1.30 (m, 3H) 1.72-2.35(m, 7H), 3.30 (s, 1H), 3.55 (m, 2H), 3.80 (m, 3H), 4.55 (m, 1H), 5.45(d, J=17.2 Hz, 1H), 5.74 (d, J=17.2 Hz, 1H), 7.15-7.70 (m, 8H), 7.92 (m,1H), 8.19 (s, 1H), 8.75 (s, 1H), 9.75 (s, 1H). LC (method 1): tR=2.17min. LC/MS (APCI) m/z: [M+H]+ 694.

1-(2-((2S,4R)-2-(3-(3-chloropyridin-2-yl)-2-fluorophenylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indazole-3-carboxamide(29)

3-Carbamoyl-1-(2-((2S,4R)-2-((3-(3-chloropyridin-2-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-5-carboxylicacid (137, 583 mg) was converted to the isocyanate compound 144 and thenreacted with 3,3-difluoropiperidine (242 mg) to afford compound 29following procedures described in Scheme 24.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.72 (m, 2H) 2.01-2.3 (m,3H), 2.60 (m, 1H), 3.52 (m, 2H), 3.79-4.40 (m, 5H), 4.77 (m, 1H),5.39-5.75 (m, 4H), 7.18-7.65 (m, 5H), 8.00 (m, 1H), 8.07 (m, 1H), 8.19(s, 1H), 8.64 (m, 1H), 8.75 (s, 1H), 10.05 (s, 1H). LC (method 1):tR=1.65 min. LC/MS (APCI) m/z: [M+H]+ 701

1-(2-((2S,4R)-2-(6-bromopyridin-2-ylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indazole-3-carboxamide(33)

1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-3-carbamoyl-1H-indazole-5-carboxylicacid (139) (533 mg) was converted to the isocyanate compound 145 andthen reacted with 3,3-difluoropiperidine (242 mg) to afford compound 33following procedures described in Scheme 24.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.72 (m, 2H) 2.01-2.3 (m,3H), 2.60 (m, 1H), 3.52 (m, 2H), 3.79-4.40 (m, 5H), 4.77 (m, 1H),5.39-5.75 (m, 4H), 7.30-7.75 (m, 4H), 8.02 (d, J=8.0 Hz, 1H), 8.28 (s,1H), 8.74 (s, 1H), 11.00 (s, 1H). LC (method 1): tR=1.59 min. LC/MS(APCI) m/z: [M+H]+ 651.

(2S,4R)-1-(2-(3-acetyl-5-(3,3-difluorocyclopentanecarboxamido)-1H-indol-1-yl)acetyl)-N-(2′-chloro-2-fluorobiphenyl-3-yl)-4-fluoropyrrolidine-2-carboxamide(30)

A mixture of 1H-indol-5-amine (220 mg),3,3-difluorocyclopentanecarboxylic acid, (250 mg), HATU (1.2 eq), andDIEA (5.0 eq) in DMF (20 mL) was stirred overnight at rt. The solventwas removed and residue purified by chromatography over silica gel toafford 3,3-difluoro-N-(1H-indol-5-yl)cyclopentanecarboxamide.

To 3,3-difluoro-N-(1H-indol-5-yl)cyclopentanecarboxamide (287 mg),acetyl chloride (1.5 eq) in DCM was added diethylaluminum chloride (1.5eq) at 0° C. The reaction mixture was stirred for 3 h and pour intoice-water and extracted with DCM. Solvent was removed and the residuewas purified by chromatography over silica gel to affordN-(3-acetyl-1H-indol-5-yl)-3,3-difluorocyclopentanecarboxamide.

N-(3-acetyl-1H-indol-5-yl)-3,3-difluorocyclopentanecarboxamide (8 mg),tert-butyl 2-bromoacetate(5.6 mg) and K₂CO₃ (4.1 mg) in ACN (10 mL) wasstirred at 60° C. for 5 h. The solvent was removed and the residue waspurified by chromatography over silica gel to afford tert-butyl2-(3-acetyl-5-(3,3-difluorocyclopentanecarboxamido)-1H-indol-1-yl)acetate.

To2-(3-acetyl-5-(3,3-difluorocyclopentanecarboxamido)-1H-indol-1-yl)acetate(7 mg) was treated with 4 N HCl in dioxane and the reaction was stirredfor 3 h at RT. The solvent was removed and the crude product was useddirectly in the next step.

2-(3-Acetyl-5-(3,3-difluorocyclopentanecarboxamido)-1H-indol-1-yl)aceticacid (5 mg) and(2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (6.3 mg) were coupled using HATU as a coupling reagent asdescribed in Scheme 14 to afford compound 30.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.92-2.70 (m, 10H) 3.19 (m,1H), 3.88-4.18 (m, 2H), 4.77 (m, 1H), 5.19 (d, J=17.2 Hz, 1H), 5.35 (d,J=17.2 Hz, 1H), 5.48 (m, 1H), 5.61 (m, 1H), 7.04-7.59 (m, 8H), 8.01 (m,1H), 8.17 (s, 2H), 8.61 (s, 1H), 10.02 (s, 1H). LC (method 1): tR=2.61min. LC/MS (APCI) m/z: [M+H]+ 683.

(2S,4R)-1-(2-(3-acetyl-5-(3,3,3-trifluoropropanamido)-1H-indol-1-yl)acetyl)-N-(2′-chloro-2-fluorobiphenyl-3-yl)-4-fluoropyrrolidine-2-carboxamide(36)

2-(3-Acetyl-5-(3,3,3-trifluoropropanamido)-1H-indol-1-yl)acetic acid(152, 10 mg) and(2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (115, 10 mg) were coupled using HATU as a coupling agentfollowing the procedures described in Scheme 8 to afford compound 36.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 2.16-2.70 (m, 4H) 3.28 (m,1H), 3.49 (ddd, J=22.4, 11.2, Hz, 2H), 3.89-4.01 (m, 1H), 4.13-4.22 (m,1H), 4.75 (m, 1H), 5.16 (d, J=17.2 Hz, 1H), 5.32 (d, J=17.2 Hz, 1H),5.43 (d, J=35.6 Hz, 1H), 7.04-7.59 (m, 8H), 8.01 (m, 1H), 8.17 (s, 2H),8.61 (s, 1H), 10.27 (s, 1H). LC (method 1): tR=2.70 min. LC/MS (APCI)m/z: [M+H]+ 661.

tert-Butyl3-acetyl-1-(2-((2S,4R)-2-(3-chloro-2-fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-6-ylcarbamate (37)

To a solution of3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (104, 56 mg) and DCM (20 mL) was added TEA (0.02 mL, 1 eq.). Thesolution was stirred for 15 min. and DPPA (0.02 mL, 1 eq.) was added.The reaction mixture was stirred for 16 h at RT and DCM was removed. Theresidue was diluted with toluene (15 mL) and excess tert-BuOH and heatedat reflux for 16 h. The solvent was evaporated and the residue waspurified by chromatography over silica gel (MeOH in DCM gradient) toobtain tert-butyl3-acetyl-1-(2-((2S,4R)-2-(3-chloro-2-fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-6-ylcarbamate(37) (46 mg, 0.08 mmol). LC (method 1): tR=1.90 min. LC/MS (APCI) m/z:[M+H]+ 589.

(2S,4R)-1-(2-(3-acetyl-5-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(39)

3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (97, 518 mg) was converted to the isocyanate and the isocyante, 98,was reacted with 2-azabicyclo[2.2.1]heptane (194 mg) to afford compound39 following procedures described in Scheme 24.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.38-1.77 (m, 6H),2.00-2.17 (m, 1H), 2.45 (s, 3H), 2.62 (s, 1H), 3.10 (d, J=10.8 Hz, 1H),3.46-3.48 (m, 1H), 3.80-4.00 (m, 1H), 4.05-4.55 (m, 5H), 5.21 (d, J=17.2Hz, 1H), 5.42 (d, J=53.2 Hz, 1H), 5.58 (s, 1H), 6.99-7.07 (m, 1H),7.15-7.45 (m, 4H), 8.15 (s, 2H), 8.27 (s, 1H), 8.59 (t, J=5.6 Hz, 1H).LC (method 1): tR=1.76 min. LC/MS (APCI) m/z: [M+H]⁺ 597.

3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-(phenylsulfonyl)-1H-indole-6-carboxamide(53)

Compound 53 was prepared from3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-6-carboxylicacid (104, 518 mg) and benzenesulfonamide (786 mg) using HATU as acoupling agent to afford compound 53 following procedures described inScheme 11.

¹H NMR (400 MHz, CD₃OD): (major rotamer) δ2.06-2.25 (m, 1H), 2.41 (s,3H), 2.51-2.59 (m, 1H), 3.82-4.15 (2H), 4.32 (m, 2H), 4.49 (m, 1H),5.13-5.45 (m, 3H), 6.62 (t, J=7.0 Hz, 1H), 7.15 (dt, J=6.4 Hz, J=7.0 Hz2H), 7.45 (t, 2H), 7.55 (m, 2H), 7.82 (d, 2H), 7.88 (s, 1H), 8.25 (m,2H), 8.59 (t, J=5.6 Hz, 1H). LC (method 1): tR=1.71 min. LC/MS (EI) m/z:[M+H]⁺ 657.

1-(2-((2S,4R)-2-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-pivalamido-1H-pyrazolo[3,4-d]thiazole-3-carboxamide(55)

Step 1: tert-Butyl(5-pivalamido-1H-pyrazolo[3,4-d]thiazol-3-yl)carbamate (154)

tert-Butyl (5-amino-1H-pyrazolo[3,4-d]thiazol-3-yl)carbamate (1.19 g,4.67 mmol) in THF (25 mL) was treated with pivaloyl chloride (2.89 mL,23.35 mmol) in the presence of pyridine (2.26 mL, 28 mmol) at 70° C. for2 h. DMEDA (2.56 mL, 23.35 mmol) was added and the mixture was stirredat 70° C. overnight. The solvent was removed by evaporation, and theresidue was treated with 5% aq. citric acid (100 mL). The formed solidwas collected by filtration, washed with water, and dried under vacuumto afford tert-butyl(5-pivalamido-1H-pyrazolo[3,4-d]thiazol-3-yl)carbamate (1.53 g).

Step 2: N-(3-Amino-1H-pyrazolo[3,4-d]thiazol-5-yl)pivalamidehydrochloride (155)

tert-Butyl (5-pivalamido-1H-pyrazolo[3,4-d]thiazol-3-yl)carbamate (1.53g, 4.5 mmol) was treated with TFA (15 mL) in DCM (30 mL) at roomtemperature for 1 h. After the volatiles are removed under reducedpressure, the residue was co-evaporated with HCl/dioxane (4 N, 10 mL)and dried under vacuum to affordN-(3-amino-1H-pyrazolo[3,4-d]thiazol-5-yl)pivalamide hydrochloride (1.78g) as a solid.

Step 3: N-(3-Iodo-1H-pyrazolo[3,4-d]thiazol-5-yl)pivalamide (156)

N-(3-Amino-1H-pyrazolo[3,4-d]thiazol-5-yl)pivalamide hydrochloride (1.78g) suspended in H₂SO₄ (1 N, 40 mL) was treated with NaNO₂ (0.47 g, 6.75mmol) in water (1 mL) at 0° C. After stirring for 10 min, KI (3.74 g,22.5 mmol) was carefully added. The dark mixture was stirred at roomtemperature for 2 h. Na₂SO₃ (2.5 g) was added with stirring. The mixturewas adjusted to pH 8-9 and extracted with EtOAc (100 mL×2). Afterwashing the organic layer with brine and drying over anhydrous Na₂SO₄,the solvent was removed by evaporation to affordN-(3-iodo-1H-pyrazolo[3,4-d]thiazol-5-yl)pivalamide (1.41 g) as a brownpowder.

Step 4: tert-Butyl2-(3-iodo-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetate (157)

A mixture of N-(3-iodo-1H-pyrazolo[3,4-d]thiazol-5-yl)pivalamide (1.41g, 4.03 mmol), tert-butyl 2-bromoacetate (0.62 mL, 4.23 mmol) and K₂CO₃was refluxed in acetonitrile (40 mL) for 4 h. The mixture was filteredand the filtrate was concentrated under reduced pressure. The remainingresidue was purified by column chromatography (silica gel,hexanes/EtOAc=1:1) to afford tert-butyl2-(3-iodo-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetate (0.706 g).

Step 5: tert-Butyl2-(3-cyano-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetate (158)

Into an argon-purged solution of tert-butyl2-(3-iodo-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetate (0.706 g,1.52 mmol) and DMF-water (15 mL/1.5 mL) was added Zn(CN)₂ (0.267 g, 2.28mmol) followed by Pd(dppf)₂ (0.124 g, 0.152 mmol) and Pd₂(dba)₃ (0.139g, 0.152 mmol). The mixture was stirred at 90° C. for 4 h. EtOAc (50 mL)was added and the mixture was filtered through a pad of Celite®. Thefiltrate was concentrated under reduced pressure and the remainingresidue was purified by column chromatography (silica gel, 40% EtOAc inhexanes) to afford tert-butyl2-(3-cyano-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetate (0.25 g)as a solid.

Step 6:2-(3-Carbamoyl-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetic acid(159)

tert-Butyl2-(3-cyano-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetate (51 mg,0.14 mmol) in TFA (1.5 mL) and water (5 μL) was heated with microwaveirradiation at 140° C. for 30 min. The volatiles were removed byevaporation and the residue was co-evaporated with toluene (5 mL) toafford 2-(3-carbamoyl-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)aceticacid which was used directly in the next synthetic step.

Step 7:1-(2-((2S,4R)-2-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-pivalamido-1H-pyrazolo[3,4-d]thiazole-3-carboxamide(55)

A mixture of2-(3-carbamoyl-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetic acidand(2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (57.5 mg, 0.154 mmol) in DMF was treated with TBTU (67.4mg, 0.321 mmol) followed by DIEA (0.122 mL, 0.7 mmol) and the reactionwas stirred at room temperature overnight. The reaction mixture waspurified by HPLC to afford1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-pivalamido-1H-pyrazolo[3,4-d]thiazole-3-carboxamide(62 mg).

¹H NMR (400 MHz, MeOD): (major rotamer) δ 1.29 (s, 9H), 2.29-2.41 (m,1H), 2.67-2.72 (m, 1H), 3.94 (ddd, J=35.8, 12.6, 3.2 Hz, 1H), 4.18 (dd,J=19.8, 12 Hz, 1H), 5.34 (dd J=34, 16.8 Hz, 2H), 5.46 (d, J=52.4 Hz,1H), 7.03-7.07 (m, 1H), 7.13 (t, J=7.6 Hz, 1H), 7.18-7.38 (m, 3H),7.45-7.48 (m, 1H), 7.96-7.99 (m, 1H). ¹⁹F NMR (376 MHz, MeOD): δ−128.50,−177.98. LC (method A): t_(R)=2.20 min. LC/MS (EI) m/z: [M+H]⁺ 644.

1-(2-((2S,4R)-2-((3-Chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-pivalamido-1H-pyrazolo[3,4-d]thiazole-3-carboxamide(56)

A mixture of2-(3-carbamoyl-5-pivalamido-1H-pyrazolo[3,4-d]thiazol-1-yl)acetic acid,159, (0.145 mmol) and(2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (65) (50 mg, 0.16 mmol) in DMF was treated with TBTU (70mg, 0.22 mmol) followed by DIEA (0.126 mL, 0.725 mmol) at roomtemperature for 2 h. The reaction mixture was purified by HPLC to afford1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-pivalamido-1H-pyrazolo[3,4-d]thiazole-3-carboxamide,56, (41 mg).

¹H NMR (400 MHz, MeOD): (major rotamer) δ 1.32 (s, 9H), 2.15-2.32 (m,1H), 2.55-2.67 (m, 1H), 3.89 (ddd, J=35.4, 12.0, 2.8 Hz, 1H), 4.08 (dd,J=20.2, 12 Hz, 1H), 4.44-4.48 (m, 2H), 5.21-5.30 (m 2H), 5.41 (d, J=52Hz, 1H), 6.93 (t, J=8 Hz, 1H), 7.20-7.40 (m, 3H), 8.49 (t, J=5.6 Hz,1H). ¹⁹F NMR (376 MHz, MeOD): δ−121.99, −177.63. LC (method A):t_(R)=1.77 min. LC/MS (EI) m/z: [M+H]+ 582.

1-(2-((2S,4R)-2-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N5-cyclopropyl-1H-thieno[3,2-c]pyrazole-3,5-dicarboxamide(57)

Step 1: Methyl 5-methylthiophene-2-carboxylate (161)

To a solution of 5-methylthiophene-2-carboxylic acid (25 g, 0.176 mol)in 300 mL of anhydrous methanol was added concentrated H₂SO₄ (3 mL). Themixture was heated at reflux for 60 h. The reaction was cooled to rt andthe solvent was removed under reduced pressure. The residue was dilutedwith ethyl acetate (200 mL) and quenched carefully with saturated aq.sodium bicarbonate (adjust pH>7). The organic layer was collected andthe aqueous phase was extracted with ethyl acetate twice. The combinedorganic solution was washed with brine, dried over MgSO₄, and filtered.The filtrate was concentrated to afford 25.8 g of the title compound asa pale yellow oil. LC (method A): t_(R)=1.70 min. LC/MS (EI) m/z: [M+H]⁺156.9.

Step 2: Methyl 5-methyl-4-nitrothiophene-2-carboxylate (162)

Methyl 5-methylthiophene-2-carboxylate (25.8 g) was dissolved in 50 mLof cold concentrated sulfuric acid and the mixture was kept cold in anice bath. To this solution, a prepared solution of fuming nitric acid(14 mL) and concentrated sulfuric acid (40 mL) was added dropwise. Aftercompletion of the addition, the mixture was stirred for an additional 15min at 0° C. The reaction mixture was poured carefully into crushed iceand the solid was collected by filtration, washed with water, and dried.The desired product (24.3 g) was used directly in the next syntheticstep.

¹H NMR (400 MHz, CDCl₃): (major isomer) δ: 2.84 (s, 3H), 3.91 (s, 3H),8.20 (s, 1H) ppm. LC (method A): t_(R)=1.73 min. LC/MS (EI) m/z: [M+H]⁺202.3.

Step 3: Methyl 4-amino-5-methylthiophene-2-carboxylate (163)

Methyl 5-methyl-4-nitrothiophene-2-carboxylate (24.3 g) was dissolved ina mixture of THF (100 mL) and methanol (100 mL) and then to thissolution was added wet Raney Ni. The solution was degassed, refilledwith hydrogen, and stirred over an atmosphere of hydrogen overnight. Themixture was filtered through a pad of Celite® and concentrated to affordthe title product (17.1 g), which was used directly in the nextsynthetic step. LC (method A): t_(R)=0.55 min. LC/MS (EI) m/z: [M+H]⁻172.2.

Step 4: Methyl 1-acetyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (164)

To a solution of methyl 4-amino-5-methylthiophene-2-carboxylate (17.0 g,0.1 mol) in 150 mL of anhydrous toluene, KOAc (5.88 g, 60 mmol) wasadded, followed by Ac₂O (17.4 g, 16.1 mL, 170 mmol). The mixture washeated at 100° C. for 3 h and then cooled to room temperature. Isoamylnitrite (12.9 g, 14.8 mL, 110 mmol) was added and the reaction washeated at 120° C. for 3 h. The reaction was cooled to rt, diluted withethyl acetate, and filtered. The filtrate was concentrated. The blacksolid residue was purified to afford the title product.

¹H NMR (400 MHz, CDCl₃): (major isomer) δ: 2.75 (s, 3H), 3.95 (s, 3H),7.94 (s, 1H), 8.22 (s, 1H) ppm. LC (method A): t_(R)=1.61 min. LC/MS(EI) m/z: [M+H]⁻ 225.0.

Step 5: Methyl 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylate (165)

To a mixture of methyl 1-acetyl-1H-thieno[3,2-c]pyrazole-5-carboxylate(1.12 g, 5 mmol) in anhydrous methanol (20 mL) was added sodiummethoxide (25% in methanol, 3 mL). The mixture was heated at 60° C. for20 min. The solution was cooled to rt, then iodine (1.4 g, 5.5 mmol) wasadded in one portion. The mixture was heated at 60° C. for 2 h, thencooled to rt. The volatiles were removed under reduced pressure, and theremaining residue was used in the next synthetic step without furtherpurification.

Step 6: Methyl1-(2-(tert-butoxy)-2-oxoethyl)-3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylate(166)

To a solution of methyl 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylate in30 mL CH₃CN was added tert-butyl 2-bromoacetate (0.8 mL, 5.5 mmol) andsolid potassium carbonate (1.5 g, 10.6 mmol). The mixture was heated atreflux overnight under an atmosphere of argon. LC-MS analysis indicatedtwo isomers were formed in a ratio of 7:3. The reaction mixture wascooled to rt and filtered through a pad of Celite®. The solid cake waswashed with CH₃CN (20 mL) and the combined filtrates were concentrated.The remaining residue was purified to afford pure separated major (1.08g) and minor isomers.

¹H NMR (400 MHz, CDCl₃): (major isomer) δ: 1.46 (s, 9H), 3.93 (s, 3H),4.96 (s, 2H), 7.67 (s, 1H) ppm. LC/MS tR=2.63 min, [M+H]⁺ 422.91. ¹H NMR(400 MHz, CDCl₃): (minor isomer) δ: 1.48 (s, 9H), 3.93 (s, 3H), 5.07 (s,2H), 7.90 (s, 1H) ppm. LC (method A): t_(R)=2.47 min. LC/MS (EI) m/z:[M+H]⁺ 423.0.

Step 7: Methyl1-(2-(tert-butoxy)-2-oxoethyl)-3-cyano-1H-thieno[3,2-c]pyrazole-5-carboxylate(167)

To a degassed solution of methyl1-(2-(tert-butoxy)-2-oxoethyl)-3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylate(1.08 g, 2.56 mmol) in DMF (25 mL) and water (3 mL) was added Zn(CN)₂(364 mg, 3.07 mmol), Pd(dppf)₂Cl₂ (212 mg, 0.26 mmol) and Pd₂(dba)₃ (238mg, 0.26 mmol) under argon. The mixture was heated at 100° C. overnight.The reaction was then cooled to rt and the volatiles were evaporatedunder reduced pressure. The residue was diluted with ethyl acetate (50mL) and filtered through a pad of Celite®. The collected solid waswashed with ethyl acetate (30 mL). The combined filtrates wereconcentrated and the remaining residue was purified to afford 364 mg ofthe title compound (168).

¹H NMR (400 MHz, CDCl₃) δ:1.48 (s, 9H), 3.95 (s, 3H), 5.03 (s, 2H), 7.67(s, 1H) ppm. LC (method A): t_(R)=2.37 min. LC/MS (EI) m/z: [M+H]⁺266.0.

Step 8:2-(3-Carbamoyl-5-(methoxycarbonyl)-1H-thieno[3,2-c]pyrazol-1-yl)aceticacid (169)

A solution of methyl1-(2-(tert-butoxy)-2-oxoethyl)-3-cyano-1H-thieno[3,2-c]pyrazole-5-carboxylate(120 mg, 0.37 mmol) in TFA (1.5 mL) and water (0.3 mL) was subjected tomicrowave irradiation at 130° C. for 30 min. The mixture wasconcentrated in vacuo and the residue was co-evaporated with toluene (10mL) twice. The dried residue was used directly in the next syntheticstep. LC (method A): t_(R)=0.61 min. LC/MS (EI) m/z: [M+H]⁺ 284.0. (169)

Step 9: Methyl3-carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylate(170)

To a solution of2-(3-carbamoyl-5-(methoxycarbonyl)-1H-thieno[3,2-c]pyrazol-1-yl)aceticacid (0.47 mmol) and(2S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamidehydrochloride(177 mg, 0.47 mmol) in DMF (2 mL) was added HATU (214 mg,0.56 mmol) followed by dropwise addition of DIEA (0.5 mL) at roomtemperature. The mixture was stirred for 1 h at rt and the volatileswere removed under reduced pressure. The residue was diluted with 20 mLof 10% sodium carbonate and extracted with ethyl acetate (3×20 mL). Thecombined organic solution was successively washed with water and brine,and dried over MgSO₄. The mixture was filtered and the filtrate wasconcentrated. The remaining residue was purified to afford the titlecompound (167.7 mg).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 2.03-2.19 (m, 1H),2.46-2.55 (m, 1H), 3.79 (s, 3H), 3.75-3.90 (m, 1H), 4.01-4.10 (m, 1H),4.70 (t, J=8.4 Hz, 1H), 5.34-5.59 (m, 3H), 7.01 (t, J=6.4 Hz, 1H), 7.15(t, J=8.0 Hz, 1H), 7.30-7.52 (m, 5H), 7.69 (s, 1H), 7.89-7.94 (m, 2H),9.92 (s, 1H) ppm; ¹⁹F NMR (376 MHz, DMSO-d₆): (major rotamer) δ −126.79,−175.78. LC (method A): t_(R)=2.10 min. LC/MS (EI) m/z: [M+H]⁺ 602.2.

Step 10:3-Carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylicacid (171)

The compound from Step 9 (110 mg, 0.18 mmol) was dissolved in a mixtureof CH₃OH-THF-H₂O (2 mL-2 mL-2 mL) and treated with LiOH (24 mg). Thereaction mixture was stirred overnight at rt. The volatiles were removedunder reduce pressure and the remaining residue was acidified with 10%citric acid (10 mL). The white solid was collected, washed with water,and dried for use in the next step.

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 2.03-2.19 (m, 1H),2.46-2.55 (m, 1H), 3.77-3.90 (m, 1H), 4.01-4.10 (m, 1H), 4.71 (t, J=8.4Hz, 1H), 5.27-5.57 (m, 3H), 7.0 (t, J=6.4 Hz, 1H), 7.15 (t, J=8.0 Hz,1H), 7.30-7.41 (m, 4H), 7.50-7.53 (m, 1H), 7.65 (s, 1H), 7.76 (s, 1H),7.93 (t, J=7.2 Hz, 1H), 9.95 (s, 1H) ppm; ¹⁹F NMR (376 MHz, DMSO-d₆):(major rotamer) δ −126.81, −175.80. LC (method A): t_(R)=1.78 min. LC/MS(EI) m/z: [M+H]⁺ 588.

Step 11:1-(2-((2S,4R)-2-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N5-cyclopropyl-1H-thieno[3,2-c]pyrazole-3,5-dicarboxamide

To a solution of3-carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylicacid (0.1 mmol) and HATU (0.15 mmol) in DMF (1 mL) was added DIEA (0.5mmol) dropwise. The mixture was stirred for 30 min at rt, thencyclopropanamine (0.2 mmol) was added. The mixture was stirred for anadditional 30 min and the volatiles were removed under reduced pressure.The solution was subjected to preparative HPLC purification to afford17.9 mg of the title compound (57).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 0.47-0.51 (m, 2H),0.61-0.65 (m, 2H), 2.01-2.18 (m, 1H), 2.36-2.54 (m, 1H), 2.73-2.78 (m,1H), 3.74-3.87 (m, 1H), 4.02-4.12 (m, 1H), 4.70 (t, J=8.4 Hz, 1H),5.24-5.55 (m, 3H), 7.0 (t, J=6.8 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H),7.30-7.40 (m, 4H), 7.50-7.52 (m, 1H), 7.62 (s, 1H), 7.67 (s, 1H), 7.91(t, J=7.2 Hz, 1H), 8.58 (m, 1H), 9.96 (s, 1H); ¹⁹F NMR (376 MHz,DMSO-d6): (major rotamer) δ −126.86, −175.74. LC (method A): t_(R)=1.96min. LC/MS (EI) m/z: [M+H]⁺ 627.1.

To a solution of3-carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylicacid (0.1 mmoL) and HATU (0.15 mmol) in DMF (1 mL) was added DIEA (0.5mmol) dropwise. The mixture was stirred for 30 min at rt, then CH₃NH₂HCl (0.2 mmol) was added. The mixture was stirred for an additional 30min and the volatiles are removed under reduced pressure. The remainingmaterial was subjected to preparative HPLC purification to afford 11.4mg of the title compound (58).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 2.01-2.18 (m, 1H),2.36-2.54 (m, 1H), 2.70 (d, J=4.4 Hz, 3H), 3.75-3.87 (m, 1H), 4.05-4.13(m, 1H), 4.70 (t, J=8.4 Hz, 1H), 5.26-5.56 (m, 3H), 7.0 (t, J=6.8 Hz,1H), 7.15 (t, J=8.0 Hz, 1H), 7.30-7.41 (m, 4H), 7.50-7.52 (m, 1H), 7.62(s, 1H), 7.66 (s, 1H), 7.91 (t, J=7.2 Hz, 1H), 8.52 (m, 1H), 9.96 (s,1H); ¹⁹F NMR (376 MHz, DMSO-d6): (major rotamer) δ −126.85, −175.81. LC(method A): t_(R)=1.82 min. LC/MS (EI) m/z: [M+H]⁺ 601.1.

1-(2-((2S,4R)-2-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(morpholine-4-carbonyl)-1H-thieno[3,2-c]pyrazole-3-carboxamide(59)

To a solution of3-carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylicacid (0.1 mmol) and HATU (0.15 mmol) in DMF (1 mL) was added DIEA (0.5mmol) dropwise. The mixture was stirred for 30 min at rt, thenmorpholine (0.2 mmol) was added. The mixture was stirred for anadditional 30 min and the volatiles are removed under reduced pressure.The remaining material was subjected to preparative HPLC purification toafford 64.7 mg of the title compound (59).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 2.02-2.1 (m, 1H), 2.36-2.59(m, 1H), 3.55-3.57 (m, 8H), 3.76-3.88 (m, 1H), 4.02-4.11 (m, 1H), 4.71(t, J=8.4 Hz, 1H), 5.30-5.53 (m, 3H), 7.0 (t, J=6.8 Hz, 1H), 7.15 (t,J=8.0 Hz, 1H), 7.31-7.43 (m, 5H), 7.51-7.53 (m, 1H), 7.64 (s, 1H), 7.89(t, J=7.6 Hz, 1H), 9.96 (s, 1H); ¹⁹F NMR (376 MHz, DMSO-d6): (majorrotamer) δ −126.75, −175.70. LC (method A): t_(R)=1.88 min. LC/MS (EI)m/z: [M+H]⁺ 657.0.

1-(2-((2S,4R)-2-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N5-cyclopentyl-1H-thieno[3,2-c]pyrazole-3,5-dicarboxamide(60)

To a solution of3-carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylicacid (0.1 mmol) and HATU (0.15 mmol) in DMF (1 mL) was added DIEA (0.5mmol) dropwise. The mixture was stirred for 30 min at rt, thenpyrrolidine (0.2 mmol) was added. The mixture was stirred for anadditional 30 min and the volatiles are removed under reduced pressure.The remaining material was subjected to preparative HPLC purification toafford 55.9 mg of the title compound (60).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.72-1.91 (m, 4H),2.02-2.19 (m, 1H), 2.36-2.57 (m, 1H), 3.43 (br, 2H), 3.68 (br, 2H),3.75-3.88 (m, 1H), 4.02-4.10 (m, 1H), 4.72 (t, J=8.4 Hz, 1H), 5.32-5.53(m, 3H), 7.0 (t, J=6.8 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.31-7.43 (m,4H), 7.51-7.53 (m, 1H), 7.61-7.62 (m, 2H), 7.90 (t, J=7.6 Hz, 1H), 9.95(s, 1H); ¹⁹F NMR (376 MHz, DMSO-d6): (major rotamer) δ −126.78, −175.67.LC (method A): t_(R)=2.01 min. LC/MS (EI) m/z: [M+H]⁺ 641.0

1-(2-((2S,4R)-2-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N5-cyclopentyl-1H-thieno[3,2-c]pyrazole-3,5-dicarboxamide(61)

To a solution of3-carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylicacid (0.1 mmol) and HATU (0.15 mmol) in DMF (1 mL) was added DIEA (0.5mmol) dropwise. The mixture was stirred for 30 min at rt, thencyclopentanamine (0.2 mmol) was added. The mixture was stirred for anadditional 30 min and the volatiles are removed under reduced pressure.The remaining material was subjected to preparative HPLC purification toafford 21.6 mg of the title compound (61).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ 1.41-1.52 (m, 4H),1.57-1.68 (m, 2H), 1.77-1.87 (m, 2H), 2.01-2.18 (m, 1H), 2.36-2.54 (m,1H), 3.74-3.87 (m, 1H), 4.04-4.15 (m, 1H), 4.70 (t, J=8.4 Hz, 1H),5.24-5.57 (m, 3H), 7.0 (t, J=6.8 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H),7.30-7.42 (m, 4H), 7.50-7.54 (m, 1H), 7.62 (s, 1H), 7.77 (s, 1H), 7.91(t, J=7.2 Hz, 1H), 8.45 (m, 1H), 9.97 (s, 1H); ¹⁹F NMR (376 MHz,DMSO-d6): (major rotamer) δ −126.86, −175.67. LC (method A): t_(R)=2.27min. LC/MS (EI) m/z: [M+H]⁺ 655.2.

1-(2-((2S,4R)-2-((2′-Chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N5,N5-dimethyl-1H-thieno[3,2-c]pyrazole-3,5-dicarboxamide(62)

To a solution of3-carbamoyl-1-(2-((2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylicacid (0.1 mmol) and HATU (0.15 mmol) in DMF (1 mL) was added DIEA (0.5mmol) dropwise. The mixture was stirred for 30 min at rt, thendimethylamine hydrochloride (0.2 mmol) was added. The mixture wasstirred for an additional 30 min and the volatiles are removed underreduced pressure. The remaining material was subjected to preparativeHPLC purification to afford 15.2 mg of the title compound (62).

¹H NMR (400 MHz, DMSO-d₆): (major rotamer) δ2.02-2.19 (m, 1H), 2.36-2.55(m, 1H), 3.03 (s, 6H), 3.76-3.89 (m, 1H), 4.02-4.10 (m, 1H), 4.71 (t,J=8.4 Hz, 1H), 5.30-5.52 (m, 3H), 7.0 (t, J=6.8 Hz, 1H), 7.16 (t, J=8.0Hz, 1H), 7.30-7.41 (m, 4H), 7.48 (s, 1H), 7.51-7.53 (m, 1H), 7.62 (s,1H), 7.89 (t, J=7.2 Hz, 1H), 9.96 (s, 1H) ppm; ¹⁹F NMR (376 MHz,DMSO-d6): (major rotamer) δ −126.75, −175.72. LC (method A): t_(R)=1.89min. LC/MS (EI) m/z: [M+H]⁺ 615.2.

3-Acetyl-N-(cyclopropylsulfonyl)-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(174)

Step 1: Methyl3-acetyl-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate

To a solution ofN-(2-((2R,4R)-4-fluoropyrrolidin-2-yl)ethyl)benzenesulfonamidehydrochloride (95) (1 equiv) in DMF (10 vol) at 0° C. under nitrogenatmosphere was added 91 (1.2 equiv), HATU (1.5 equiv) and DIPEA (5equiv). The reaction mixture was stirred at room temperature for 16 h.After completion of the reaction, the reaction mixture was quenched withwater (30 vol). The resulting solid was filtered and dried to givemethyl 3-acetyl-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(172).

Step 2:3-acetyl-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (173)

To a solution of methyl3-acetyl-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate.(1 equiv) in THF/water (8:2) was added LiOH (4 equiv). The reactionmixture was stirred at room temperature for 4 h and then quenched with 1M citric acid. The resulting mixture was extracted with ethyl acetate.The organic layer was separated, dried over anhydrous Na₂SO₄, filteredand then concentrated to give methyl3-acetyl-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate.

Step 3:3-acetyl-N-(cyclopropylsulfonyl)-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(173)

To a solution of methyl3-acetyl-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(1 equiv) in THF (10 vol) was added CDI (2 equiv). The reaction mixturewas stirred at 70° C. for 4 h and then cooled to room temperature.Cyclopropylsulfonamide (2 equiv) and DBU (2.5 equiv) was added to thereaction mixture and the reaction mixture was stirred at roomtemperature for 16 h. After completion of the reaction, the reactionmixture was quenched with water (30 vol). The resulting mixture wasextracted with DCM. The organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and then concentrated. The residue waspurified by column chromatography on silica gel using DCM/MeOH to give3-acetyl-N-(cyclopropylsulfonyl)-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(174).

¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H), 8.82 (s, 1H), 8.40 (s, 1H),7.89-7.73 (m, 3H), 7.68-7.51 (m, 5H), 5.51-5.28 (m, 2H), 5.26-5.08 (m,1H), 4.10-3.96 (m, 2H), 3.80-3.70 (m, 1H), 3.20-3.16 (m, 1H), 2.73-2.71(m, 2H), 2.38 (s, 3H), 2.06-2.04 (m, 1H), 1.97-1.77 (m, 2H), 1.52-1.49(m, 1H), 1.22-1.06 (m, 4H).

(2S,4R)—N-Benzyl-4-fluoropyrrolidine-2-carboxamide hydrochloride (176)

To a solution of 63 (1 equiv) in DMF (10 vol) at 0° C. under nitrogenatmosphere was added benzyl amine (1.2 equiv), HATU (1.5 equiv) andDIPEA (3 equiv). The reaction mixture was stirred at room temperaturefor 3 h. After completion of the reaction, the reaction mixture wasquenched with water (30 vol). The resulting mixture was extracted withDCM. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and then concentrated. The residue was purified bycolumn chromatography on silica gel using DCM/MeOH to afford 45b. To asolution of 45b (1 equiv) in 1,4-dioxane (3 vol) at 0° C. under nitrogenatmosphere was added 4 N HCl in 1,4-dioxane (10 vol) and stirred at roomtemperature for 3 h. The reaction mixture was concentrated to afford176.

3-Acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-(cyclopropylsulfonyl)-1H-indole-5-carboxamide(180)

Step 1: Methyl3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(178)

To a solution of (2S,4R)—N-benzyl-4-fluoropyrrolidine-2-carboxamidehydrochloride (1 equiv) in DMF (10 vol) at 0° C. under nitrogenatmosphere was added Compound 176 (1.2 equiv), HATU (1.5 equiv) andDIPEA (5 equiv). The reaction mixture was stirred at room temperaturefor 16 h. After completion of the reaction, the reaction mixture wasquenched with water (30 vol). The resulting solid was filtered, dried togive methyl3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(178).

Step 2:3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (179)

To a solution of methyl3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(1 equiv) in THF/water (8:2) was added LiOH (4 equiv). The reactionmixture was stirred at room temperature for 4 h and then quenched with 1M citric acid. The resulting mixture was extracted with ethyl acetate.The organic layer was separated, dried over anhydrous Na₂SO₄, filteredand then concentrated to give3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid.

Step 3:3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-(cyclopropylsulfonyl)-1H-indole-5-carboxamide(180)

To a solution of3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (1 equiv) in THF (10 vol) was added CDI (2 equiv). The reactionmixture was stirred at 70° C. for 4 h and then cooled to roomtemperature. Cyclopropylsulfonamide (2 equiv) and DBU (2.5 equiv) wasadded to the reaction mixture and the reaction mixture was stirred atroom temperature for 16 h. After completion of the reaction, thereaction mixture was quenched with water (30 vol). The resulting mixturewas extracted with DCM. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, filtered and then concentrated. The residue waspurified by column chromatography on silica gel using DCM/MeOH to give3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-N-(cyclopropylsulfonyl)-1H-indole-5-carboxamide(180).

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.55-8.52 (m, 1H), 8.37 (s,1H), 7.79 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.34-7.30 (m, 1H),7.23-7.18 (m, 4H), 5.58-5.43 (m, 2H), 5.27-5.23 (m, 1H), 4.47-4.10 (m,4H), 4.10-3.98 (m, 1H), 3.17-3.14 (m, 1H), 2.49 (s, 3H), 2.48-2.47 (m,1H), 2.20-2.01 (m, 1H), 1.15-1.11 (m, 4H).

(2S,4R)-4-Fluoro-N-phenethylpyrrolidine-2-carboxamide hydrochloride(182)

To a solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1equiv) in DMF (10 vol) at 0° C. under nitrogen atmosphere was added2-phenylethan-1-amine (1.2 equiv), HATU (1.5 equiv) and DIPEA (3 equiv).The reaction mixture was stirred at room temperature for 3 h. Aftercompletion of the reaction, the reaction mixture was quenched with water(30 vol). The resulting mixture was extracted with DCM. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, filtered andthen concentrated. The residue was purified by column chromatography onsilica gel using DCM/MeOH to afford tert-butyl(2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidine-1-carboxylate. To asolution of tert-butyl(2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidine-1-carboxylate (1equiv) in 1,4-dioxane (3 vol) at 0° C. under nitrogen atmosphere wasadded 4 N HCl in 1,4-dioxane (10 vol) and stirred at room temperaturefor 3 h. The reaction mixture was concentrated to afford(2S,4R)-4-fluoro-N-phenethylpyrrolidine-2-carboxamide hydrochloride(182).

3-Acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(185)

Step 1: Methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(183)

To a solution of (2S,4R)-4-fluoro-N-phenethylpyrrolidine-2-carboxamidehydrochloride (1 equiv) in DMF (10 vol) at 0° C. under nitrogenatmosphere was added Compound 182 (1.2 equiv), HATU (1.5 equiv) andDIPEA (5 equiv). The reaction mixture was stirred at room temperaturefor 16 h. After completion of the reaction, the reaction mixture wasquenched with water (30 vol). The resulting solid was filtered, dried togive methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate.

Step 2:3-Acetyl-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (184)

To a solution of methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(1 equiv) in THF/water (8:2) was added LiOH (4 equiv). The reactionmixture was stirred at room temperature for 4 h and then quenched with 1M citric acid. The resulting mixture was extracted with ethyl acetate.The organic layer was separated, dried over anhydrous Na₂SO₄, filteredand then concentrated to give3-acetyl-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid.

Step 3:3-acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(185)

To a solution of3-acetyl-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (1 equiv) in THF (10 vol) was added CDI (2 equiv). The reactionmixture was stirred at 70° C. for 4 h and then cooled to roomtemperature. Cyclopropylsulfonamide (2 equiv) and DBU (2.5 equiv) wasadded to the reaction mixture and the reaction mixture was stirred atroom temperature for 16 h. After completion of the reaction, thereaction mixture was quenched with water (30 vol). The resulting mixturewas extracted with DCM. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, filtered and then concentrated. The residue waspurified by column chromatography on silica gel using DCM/MeOH to give3-acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide.

¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H),8.12 (d, J=5.7 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H),7.20-7.14 (m, 5H), 5.59-5.32 (m, 2H), 5.29-5.10 (m, 1H), 4.35 (t, J=8.5Hz, 1H), 4.15-4.06 (m, 1H), 3.93-3.81 (m, 1H), 3.56-3.35 (m, 1H),3.31-3.08 (m, 1H), 2.65-2.64 (m, 2H), 2.48 (s, 3H), 2.39-2.37 (m, 1H),2.07-1.87 (m, 1H), 1.11-1.05 (m, 5H).

(2S,4R)-4-Fluoro-N-(3-phenylpropyl)pyrrolidine-2-carboxamidehydrochloride(187)

To a solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1equiv) in DMF (10 vol) at 0° C. under nitrogen atmosphere was added3-phenylpropan-1-amine (1.2 equiv), HATU (1.5 equiv) and DIPEA (3equiv). The reaction mixture was stirred at room temperature for 3 h.After completion of the reaction, the reaction mixture was quenched withwater (30 vol). The resulting mixture was extracted with DCM. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and then concentrated. The residue was purified by columnchromatography on silica gel using DCM/MeOH to afford tert-butyl(2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidine-1-carboxylate.To a solution of tert-butyl(2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidine-1-carboxylate(1 equiv) in 1,4-dioxane (3 vol) at 0° C. under nitrogen atmosphere wasadded 4 N HCl in 1,4-dioxane (10 vol) and stirred at room temperaturefor 3 h. The reaction mixture was concentrated to afford2S,4R)-4-fluoro-N-(3-phenylpropyl)pyrrolidine-2-carboxamidehydrochloride(187).

3-Acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(190)

Step 1: Methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(188)

To a solution of(2S,4R)-4-fluoro-N-(3-phenylpropyl)pyrrolidine-2-carboxamidehydrochloride(1 equiv) in DMF (10 vol) at 0° C. under nitrogen atmosphere was added187 (1.2 equiv), HATU (1.5 equiv) and DIPEA (5 equiv). The reactionmixture was stirred at room temperature for 16 h. After completion ofthe reaction, the reaction mixture was quenched with water (30 vol). Theresulting solid was filtered, dried to give methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate.

Step 2:3-Acetyl-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (189)

To a solution of methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(1 equiv) in THF/water (8:2) was added LiOH (4 equiv). The reactionmixture was stirred at room temperature for 4 h and then quenched with 1M citric acid. The resulting mixture was extracted with ethyl acetate.The organic layer was separated, dried over anhydrous Na₂SO₄, filteredand then concentrated to give3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid.

Step 3:3-Acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(190)

To a solution of3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (1 equiv) in THF (10 vol) was added CDI (2 equiv). The reactionmixture was stirred at 70° C. for 4 h and then cooled to roomtemperature. Cyclopropylsulfonamide (2 equiv) and DBU (2.5 equiv) wasadded to the reaction mixture and the reaction mixture was stirred atroom temperature for 16 h. After completion of the reaction, thereaction mixture was quenched with water (30 vol). The resulting mixturewas extracted with DCM. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, filtered and then concentrated. The residue waspurified by column chromatography on silica gel using DCM/MeOH to give3-acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(190).

¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 8.81 (s, 1H), 8.38 (s, 1H),8.04-8.03 (m, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H),7.20-7.05 (m, 5H), 5.47-5.42 (m, 2H), 5.27-5.23 (m, 1H), 4.60-4.38 (m,2H), 4.35-3.81 (m, 3H), 3.18-3.00 (m, 3H), 2.50-2.32 (m, 3H), 2.11-1.90(m, 2H), 1.81-1.60 (m, 2H), 1.17-1.16 (m, 4H).

(2S,4R)-4-Fluoro-N-(4-phenylbutyl)pyrrolidine-2-carboxamide (192)

To a solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1equiv) in DMF (10 vol) at 0° C. under nitrogen atmosphere was added4-phenylbutan-1-amine (1.2 equiv), HATU (1.5 equiv) and DIPEA (3 equiv).The reaction mixture was stirred at room temperature for 3 h. Aftercompletion of the reaction, the reaction mixture was quenched with water(30 vol). The resulting mixture was extracted with DCM. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, filtered andthen concentrated. The residue was purified by column chromatography onsilica gel using DCM/MeOH to afford tert-butyl(2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidine-1-carboxylate.To a solution of tert-butyl(2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidine-1-carboxylate(1 equiv) in 1,4-dioxane (3 vol) at 0° C. under nitrogen atmosphere wasadded 4 N HCl in 1,4-dioxane (10 vol) and stirred at room temperaturefor 3 h. The reaction mixture was concentrated to afford(2S,4R)-4-fluoro-N-(4-phenylbutyl)pyrrolidine-2-carboxamide.

3-acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(195)

Step 1: Methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(193)

To a solution of(2S,4R)-4-fluoro-N-(4-phenylbutyl)pyrrolidine-2-carboxamide (1 equiv) inDMF (10 vol) at 0° C. under nitrogen atmosphere was added Compound 192(1.2 equiv), HATU (1.5 equiv) and DIPEA (5 equiv). The reaction mixturewas stirred at room temperature for 16 h. After completion of thereaction, the reaction mixture was quenched with water (30 vol). Theresulting solid was filtered, dried to give methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate.

Step 2:3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (194)

To a solution of methyl3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(1 equiv) in THF/water (8:2) was added LiOH (4 equiv). The reactionmixture was stirred at room temperature for 4 h and then quenched with 1M citric acid. The resulting mixture was extracted with ethyl acetate.The organic layer was separated, dried over anhydrous Na₂SO₄, filteredand then concentrated to give3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid.

Step 3:3-acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide(195)

To a solution of3-acetyl-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (1 equiv) in THF (10 vol) was added CDI (2 equiv). The reactionmixture was stirred at 70° C. for 4 h and then cooled to roomtemperature. Cyclopropylsulfonamide (2 equiv) and DBU (2.5 equiv) wasadded to the reaction mixture and the reaction mixture was stirred atroom temperature for 16 h. After completion of the reaction, thereaction mixture was quenched with water (30 vol). The resulting mixturewas extracted with DCM. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, filtered and then concentrated. The residue waspurified by column chromatography on silica gel using DCM/MeOH to give3-acetyl-N-(cyclopropylsulfonyl)-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxamide.

¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 8.81 (s, 1H), 8.38 (s, 1H),7.97 (t, J=5.7 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H),7.25-7.05 (m, 5H), 5.59-5.38 (m, 2H), 5.24 (d, J=17.2 Hz, 1H), 4.34 (t,J=8.4 Hz, 1H), 4.21-4.11 (m, 1H), 3.95-3.75 (m, 1H), 3.20-2.96 (m, 3H),2.46 (s, 3H), 2.45-2.33 (m, 3H), 2.11-1.94 (m, 1H), 1.50-1.46 (m, 2H),1.37-1.33 (m, 2H), 1.12-1.07 (m, 4H)

N-(3-acetyl-1-(2-((2S,4R)-2-(benzylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(196)

To a solution of compound 179 (1 equiv) in benzene (10 vol) was addedTEA (1.5 equiv) and DPPA (1.2 equiv). The reaction mixture was stirredat 50° C. for 1 h and then cooled to room temperature.3,3-difluoropiperidine hydrochloride (4 equiv) and TEA (8 equiv) wasadded to the reaction mixture and stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated andthe residue was purified by preparative HPLC to give compound 196.

¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.57-8.55 (m, 1H), 8.20-8.17(m, 2H), 7.36-7.20 (m, 6H), 5.56-5.43 (m, 1H), 5.35-5.31 (m, 1H),5.15-5.11 (m, 1H), 4.46-4.40 (m, 1H), 4.29 (d, J=5.9 Hz, 1H), 4.25 (d,J=5.6 Hz, 1H), 3.80-3.77 (m, 3H), 3.52-3.51 (m, 4H), 2.40 (s, 3H),2.09-2.02 (m, 3H), 1.72-1.71 (m, 2H).

N-(3-Acetyl-1-(2-((2S,4R)-4-fluoro-2-(phenethylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(197)

To a solution of compound 184 (1 equiv) in benzene (10 vol) was addedTEA (1.5 equiv) and DPPA (1.2 equiv). The reaction mixture was stirredat 50° C. for 1 h and then cooled to room temperature.3,3-difluoropiperidine hydrochloride (4 equiv) and TEA (8 equiv) wasadded to the reaction mixture and stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated andthe residue was purified by preparative HPLC to give compound 197.

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.16 (s, 1H), 8.12-8.07 (m,1H), 7.39-7.13 (m, 7H), 5.51-5.38 (m, 1H), 5.30-5.26 (m, 1H), 5.12-5.08(m, 1H), 4.35-4.31 (m, 2H), 4.13-3.81 (m, 2H), 3.78-3.76 (m, 2H),3.51-3.50 (m, 2H), 3.29-3.16 (m, 2H), 2.66-2.65 (m, 2H), 2.40 (s, 3H),2.06-2.00 (m, 3H), 1.69-1.68 (m, 2H).

N-(3-Acetyl-1-(2-((2S,4R)-4-fluoro-2-((3-phenylpropyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(198)

To a solution of compound 189 (1 equiv) in benzene (10 vol) was addedTEA (1.5 equiv) and DPPA (1.2 equiv). The reaction mixture was stirredat 50° C. for 1 h and then cooled to room temperature.3,3-difluoropiperidine hydrochloride (4 equiv) and TEA (8 equiv) wasadded to the reaction mixture and stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated andthe residue was purified by preparative HPLC to give compound 198.

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.19-8.15 (m, 2H), 8.04-8.01(m, 1H), 7.39-7.08 (m, 6H), 5.51-5.41 (m, 1H), 5.32-5.27 (m, 1H),5.13-5.09 (m, 1H), 4.37-4.33 (m, 2H), 4.18-3.90 (m, 2H), 3.82-3.76 (m,2H), 3.52-3.49 (m, 2H), 3.06-2.99 (m, 2H), 2.59-2.58 (m, 2H), 2.36 (s,3H), 2.09-1.99 (m, 3H), 1.70-1.60 (m, 4H).

N-(3-Acetyl-1-(2-((2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(199)

To a solution of compound 194 (1 equiv) in benzene (10 vol) was addedTEA (1.5 equiv) and DPPA (1.2 equiv). The reaction mixture was stirredat 50° C. for 1 h and then cooled to room temperature.3,3-difluoropiperidine hydrochloride (4 equiv) and TEA (8 equiv) wasadded to the reaction mixture and stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated andthe residue was purified by preparative HPLC to give compound 199.

¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.19-8.16 (m, 2H), 7.96-7.95(m, 1H), 7.42-7.07 (m, 6H), 5.51-5.41 (m, 1H), 5.31-5.27 (m, 1H),5.13-5.09 (m, 1H), 4.34-4.33 (m, 2H), 4.18-3.84 (m, 2H), 3.83-3.80 (m,2H), 3.52-3.51 (m, 2H), 3.07-2.99 (m, 2H), 2.46-2.44 (m, 2H), 2.40 (s,3H), 2.08-2.03 (m, 3H), 1.71-1.70 (m, 2H), 1.53-1.49 (m, 2H), 1.38-1.34(m, 2H), 1.24-1.23 (m, 2H).

N-(3-Acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(40)

To a solution of compound 97 (1 equiv) in benzene (10 vol) was added TEA(1.5 equiv) and DPPA (1.2 equiv). The reaction mixture was stirred at50° C. for 1 h and then cooled to room temperature.3,3-difluoropiperidine hydrochloride (4 equiv) and TEA (8 equiv) wasadded to the reaction mixture and stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated andthe residue was purified by preparative HPLC to give compound 40.

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.18-8.11 (s, 2H), 7.42-7.20(m, 4H), 7.01-6.97 (m, 1H), 5.55-5.42 (m, 1H), 5.34-5.30 (m, 1H),5.14-5.09 (m, 1H), 4.48-4.23 (m, 3H), 4.14-4.08 (m, 1H), 3.93-3.76 (m,4H), 3.52-3.51 (m, 2H), 2.49 (s, 3H), 2.09-1.99 (m, 3H), 1.71-1.69 (m,2H).

N-(3-Acetyl-1-(2-((2R,4R)-4-fluoro-2-(2-(phenylsulfonamido)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(201)

To a solution of compound 173 (1 equiv) in benzene (10 vol) was addedTEA (1.5 equiv) and DPPA (1.2 equiv). The reaction mixture was stirredat 50° C. for 1 h and then cooled to room temperature.3,3-difluoropiperidine hydrochloride (4 equiv) and TEA (8 equiv) wasadded to the reaction mixture and stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated andthe residue was purified by preparative HPLC to give compound 201.

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.19 (s, 2H), 7.76 (d, J=7.2Hz, 2H), 7.63-7.54 (m, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.27 (d, J=8.8 Hz,1H), 5.43-5.19 (m, 2H), 5.09-5.05 (m, 1H), 4.06-4.03 (m, 2H), 3.84-3.78(m, 3H), 3.52-3.51 (m, 2H), 2.74-2.67 (m, 2H), 2.41 (s, 3H), 2.09-2.02(m, 3H), 1.92-1.71 (m, 4H), 1.49-1.48 (m, 1H).

(S)—N-(3-Acetyl-1-(2-(2-((6-methylpyridin-2-yl)carbamoyl)azetidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(205)

Step 1: Methyl(S)-3-acetyl-1-(2-(2-((6-methylpyridin-2-yl)carbamoyl)azetidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylate(203)

To a solution of 202 (1 equiv) in DMF (10 vol) at 0° C. under nitrogenatmosphere was added INT-9 (1.2 equiv), HATU (1.5 equiv) and DIPEA (3equiv). The reaction mixture was stirred at room temperature for 3 h.After completion of the reaction, the reaction mixture was quenched withwater (30 vol). The resulting mixture was extracted with DCM. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and then concentrated. The residue was purified by columnchromatography on silica gel using DCM/MeOH to give compound 203.

Step 2:(S)-3-Acetyl-1-(2-(2-((6-methylpyridin-2-yl)carbamoyl)azetidin-1-yl)-2-oxoethyl)-1H-indole-5-carboxylicacid (204)

To a solution of compound 203 (1 equiv) in THF/water (8:2) was addedLiOH (4 equiv). The reaction mixture was stirred at room temperature for4 h and then quenched with 1 M citric acid. The resulting mixture wasextracted with ethyl acetate. The organic layer was separated, driedover anhydrous Na₂SO₄, filtered and then concentrated to give compound204.

Step 3:(S)—N-(3-Acetyl-1-(2-(2-((6-methylpyridin-2-yl)carbamoyl)azetidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)-3,3-difluoropiperidine-1-carboxamide(205)

To a solution of compound 204 (1 equiv) in benzene (10 vol) was addedTEA (1.5 equiv) and DPPA (1.2 equiv). The reaction mixture was stirredat 50° C. for 1 h and then cooled to room temperature.3,3-difluoropiperidine hydrochloride (4 equiv) and TEA (8 equiv) wasadded to the reaction mixture and stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated andthe residue was purified by preparative HPLC to give compound 205.

¹H NMR (400 MHz, CD₃OD) δ 8.17-8.16 (m, 2H), 7.98-7.85 (m, 1H),7.75-7.71 (m, 1H), 7.41-7.35 (m, 2H), 7.05-7.02 (m, 1H), 5.09-4.99 (m,3H), 4.28-4.27 (m, 2H), 3.81-3.78 (m, 2H), 3.59-3.57 (m, 2H), 2.52 (s,3H), 2.47 (s, 3H), 2.36-2.34 (m, 1H), 2.13-2.04 (m, 3H), 1.84-1.83 (m,2H).

(1R,3S,4S)—N-(6-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamidehydrochloride (218)

Step 1: (R,E)-ethyl 2-((1-phenylethyl)imino)acetate (211)

To a solution of compound 210 (15 g, 0.12 mol) in diethyl ether (200 mL)was added Na₂SO₄ (42.6 g, 0.3 mol) and ethyl glyoxalate (18.36 g, 0.12mmol) at 0° C. The reaction mixture was stirred at room temperature for16 hrs. The reaction filtered and the filtrated was concentrated underreduced pressure to give 2 (23 g, 90.6% yield) as a colorless oil.

Step 2: (1S,3S,4R)-ethyl2-((R)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (212)

To a solution of compound 211 (23 g, 0.11 mol) in DMF (200 mL) was added1,3-cyclopentadiene (18.48 g, 0.24 mmol) and trifluoroacetic acid (16 g,0.14 mmol) at 0° C. The reaction mixture was stirred at room temperaturefor 16 hrs The mixture was diluted with EtOAc and washed with 10% aq.LiCl solution and brine successively, dried over anhydrous Na₂SO₄,filtered and then concentrated. The residue was purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=60:1) to give the title compound 212 (17 g, 57% yield) as acolorless oil. LC/MS (ESI) m/z: 272 [M+H]⁺.

Step 3: (1R,3S,4S)-ethyl2-((R)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (213)

To a solution of compound 212 (6 g, 22.1 mmol) in EtOH (60 mL) was addedPd/C (5% wt, 0.3 g) and the mixture was degassed under N₂ atmosphere forthree times and stirred under H₂ balloon at room temperature for 1 hr.After filtration through Celite, the filter cake was washed with EtOH.To the filtrate, conc. HCl solution (7 mL) was added and then theresulting mixture was concentrated to dryness under reduced pressure.This procedure was repeated several times until a semi-crystallineresidue was formed. The residue was precipitated in Et₂O/i-PrOH (50 mL,5:1) at 0° C. for 1 hr and filtered. The filter cake was dried undervacuum to give the title compound (213) (5 g, 82.8% yield) as whitesolid. LC/MS (ESI) m/z: 274 [M+H]⁺.

Step 4: (1R,3S,4S)-Ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (214)

To a solution of compound 213 (5 g, 18.3 mmol) in ethanol (10 mL) wasdegassed under N₂ atmosphere for three times and Pd(OH)₂ (500 mg, 10%wt) was added. The mixture was degassed again and stirred under H₂balloon at room temperature for 16 hrs. The mixture was filtered and thefiltrate was concentrated under reduced pressure to give the titlecompound (3.3 g, 98.5% yield) as a colorless oil. LC/MS (ESI) m/z: 170[M+H]⁺.

Step 5: (1R,3S,4S)-2-tert-Butyl 3-ethyl2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (215)

To a solution of compound 214 (3.3 g, 18 mmol) was in DCM (30 mL) wasadded triethylamine (7.5 mL, 54 mmol) and di-tert-butyl dicarbonate(7.85 g, 36 mmol) at room temperature. The reaction mixture was stirredat room temperature for 16 hrs and then diluted with DCM. The resultingmixture was washed with water and brine, dried over anhydrous Na₂SO₄,filtered and then concentrated. The residue was purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=20:1) to give the title compound (3.6 g, 71% yield) as acolorless oil. LC/MS (ESI) m/z: 214 [M+H-56]⁺.

Step 6:(1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (216)

To a solution of compound 215 (3.6 g, 0.18 mmol) in THF (20 mL) and wasadded aq. NaOH solution (2 M, 27 mL, 0.54 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 16 hrs and washedwith ethyl acetate (20 mL×2). The aqueous phase was acidified to pH=3with aq. HCl (1 M) and extracted with DCM twice. The combined organicphases are dried over anhydrous Na₂SO₄, filtered and then concentratedto give the title compound (216) (3.2 g, 99.2% yield) as white solid.LC/MS (ESI) m/z: 186 [M+H-56]⁺.

Step 7:(1R,3S,4S)-tert-butyl3-((6-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(217)

To a solution of compound 216 (2 g, 8.3 mmol) was in 1,2-Dichloroethane(20 ml) was added N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (4.1 g,16.6 mmol) and 2-Amino-6-methylpyridine (0.9 g, 8.3 mmol) at 0° C. Thereaction mixture was stirred at 85° C. for 16 hrs and concentrated todryness to give crude product, which was purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=10:1) to give the title compound (2.1 g, 79% yield) as whitesolid. LC/MS (ESI) m/z: 276 [M+H-56]⁺.

Step 8:(1R,3S,4S)—N-(6-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(218)

To a solution compound 217 (2.1 g, 6.5 mmol) in dioxane (15 mL) wasadded HCl dioxane solutions (15 mL) was at 0° C. The reaction wasstirred at room temperature for 3 hrs and concentrated to dryness togive compound INT-5 (2.3 g, 99.7% yield) as yellow solid, which wasdirectly used to the next reaction without purification. LC/MS (ESI)m/z: 232 [M+H]⁺.

2-(3-Carbamoyl-5-(cyclopropylsulfonylcarbamoyl)-1H-indol-1-yl)aceticacid (229)

Step 1: tert-Butyl 5-bromo-1H-indole-1-carboxylate (220)

A mixture of 5-bromo-1H-indole (10.0 g, 51.0 mmol), Boc₂O (16.7 g, 76.5mmol), TEA (14.2 mL, 102.0 mmol) and DMAP (622 mg, 5.1 mmol) in DCM (150mL) was stirred at room temperature for 16 hrs. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography on silica gel (PE:EtOAc=50:1) to give the title compound(14.6 g, 97.0% yield) as white solid.

Step 2: tert-Butyl 5-bromo-3-carbamoyl-1H-indole-1-carboxylate (221)

To a solution of tert-butyl 5-bromo-1H-indole-1-carboxylate (5.0 g, 16.9mmol) in dry CH₃CN (60 mL) was added sulfurwasocyanatidic chloride (1.55mL, 17.7 mmol) dropwise at 0° C. under N₂ atmosphere. Then the reactionwas stirred at room temperature for 16 hrs, followed by addition ofacetone (100 mL) and water (12 mL). The resulting mixture was basifiedwith 10% aq. NaOH solution and extracted with EtOAc (50 mL*2). Thecombined organic phases are dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was re-crystallizedwith EtOAc to afford the desired product (221) (3.6 g, 63.1% yield) aswhite solid.

Step 3: 5-Bromo-1H-indole-3-carboxamide (222)

To a solution of tert-butyl 5-bromo-3-carbamoyl-1H-indole-1-carboxylate(3.0 g) in DCM (30 mL) at 0° C. was added TFA (10 mL). The reaction wasstirred at room temperature for 2 hrs and then filtered. The filter cakewas dried under vacuum to give the title compound (3.5 g, TFA salt) aswhite solid, which was directly used to the next reaction withoutpurification.

Step 4: Methyl 3-carbamoyl-1H-indole-5-carboxylate (223)

A mixture of 5-bromo-1H-indole-3-carboxamide (3.5 g, 10.41 mmol),Pd(OAc)₂ (108 mg, 0.48 mmol), TEA (2.8 mL, 19.2 mmol) and Xant-phos (347mg, 0.60 mmol) in MeOH (10 mL) and DMF (50 mL) was degassed under N₂atmosphere for three times and the reaction mixture was stirred at 100°C. under 45 psi of CO atmosphere for 16 hrs. The mixture was filteredand the residue was evaporated under reduced pressure. The residue waspurified by chromatography on silica gel (DCM:MeOH=50:1 to 40:1) to givethe title compound (223) (1.2 g, 52.82% yield) as yellow solid.

Step 5: 3-Carbamoyl-1H-indole-5-carboxylic acid (224)

To a solution of methyl 3-carbamoyl-1H-indole-5-carboxylate (1.2 g, 5.5mmol) in MeOH (5 mL) and THF (5 mL) was added 2 M aq. NaOH solution (5.5mL) and the reaction mixture was stirred at 60° C. for 2 hr. Thevolatility was removed under reduced pressure and the mixture was washedwith EtOAc twice. The aqueous layer was acidified with 2 M aq. HCl untilpH=˜3. The slurry was filtered and the filter cake was dried undervacuum to give the title compound (224) (650 mg, 57.88% yield) as whitesolid.

Step 6: 1-(tert-Butoxycarbonyl)-3-carbamoyl-1H-indole-5-carboxylic acid(225)

A mixture of 224 (500 mg, 2.45 mmol), Boc₂O (801 mg, 3.67 mmol), TEA(0.85 mL, 6.13 mmol) and DMAP (30 mg, 0.25 mmol) in THF (15 mL) wasstirred at room temperature overnight. The mixture was evaporated underreduced pressure and the residue was purified by chromatography onsilica gel (DCM:MeOH=50:1 to 10:1) to give the title compound (224) (350mg, 47.0% yield) as white solid.

Step 7: tert-Butyl3-carbamoyl-5-((cyclopropylsulfonyl)carbamoyl)-1H-indole-1-carboxylate(226)

To a mixture of 225 (350 mg, 1.15 mmol), DIPEA (0.6 mL, 3.45 mmol) andDMAP (12.2 mg, 0.1 mmol) in dry DCM (5 mL) at 0° C. was added a solutionof trwasyl chloride (418 mg, 1.38 mmol) in DCM (5 mL) and the reactionwas stirred at 0° C. for 30 min. Then to the mixture was addedcyclopropane sulfonamide (209 mg, 1.73 mmol) and the mixture was stirredat room temperature overnight. The reaction was quenched with AcOH (0.5mL). The mixture was diluted with DCM and washed with water, brine,dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel (DCM:MeOH=50:1 to 30:1) to givethe title compound (225) (230 mg, 49.08% yield) as yellow solid.

Step 8: N5-(cyclopropylsulfonyl)-1H-indole-3,5-dicarboxamide (227)

To a solution of tert-butyl3-carbamoyl-5-((cyclopropylsulfonyl)carbamoyl)-1H-indole-1-carboxylate(230 mg, 0.564 mmol) in DCM (6 mL) was added TFA (2 mL) and the reactionwas stirred at room temperature for 1 hr. The mixture was evaporated togive the title compound (350 mg, 100% yield) as yellow solid, which wasdirectly used to the next reaction without further purification.

Step 9: tert-Butyl2-(3-carbamoyl-5-((cyclopropylsulfonyl)carbamoyl)-1H-indol-1-yl) acetate(228)

A mixture of 227 (350 mg, 0.564 mmol), tert-butyl 2-bromoacetate (143mg, 0.733 mmol), K₂CO₃ (117 mg, 0.85 mmol) in DMF (10 mL) was stirred atroom overnight. The mixture was diluted with EtOAc and washed with aq.LiCl solution. The organic phase was dried over anhydrous Na₂SO₄ andevaporated under reduced pressure. The residue was purified bychromatography on silica gel (DCM:MeOH=50:1 to 30:1) to afford thedesired product (170 mg, 71.51% yield) as white solid.

Step 10:2-(3-Carbamoyl-5-((cyclopropylsulfonyl)carbamoyl)-1H-indol-1-yl)aceticacid (229)

To a solution of tert-butyl2-(3-carbamoyl-5-((cyclopropylsulfonyl)carbamoyl)-1H-indol-1-yl) acetate(170 mg) in DCM (2 mL) was added TFA (1 mL) and the reaction was stirredat room temperature for 16 hrs. The mixture was evaporated under reducedto give 229 (190 mg, 100% yield) as yellow solid, which was directlyused to the next reaction without further purification.

N⁵-(cyclopropylsulfonyl)-1-(2-((1R,3S,4S)-3-((6-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-1H-indole-3,5-dicarboxamide(209)

To a mixture of2-(3-carbamoyl-5-((cyclopropylsulfonyl)carbamoyl)-1H-indol-1-yl)aceticacid (30 mg, 0.082 mmol),(1R,3S,4S)—N-(6-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamidehydrochloride (23 mg, 0.086 mmol) in DMF (2 mL) at 0° C. was added DIPEA(0.04 mL, 0.246 mmol) followed by HATU (46.7 mmol, 0.123 mmol). Thereaction was stirred at room temperature for 16 hrs. The mixture wasdiluted with 10% aq. LiCl solution (10 mL) and extracted withi-PrOH/CHC13 (10 mL*3, 3/1). The combined organic layers are dried overanhydrous Na₂SO₄ and concentrated to dryness. The residue was purifiedby preparative HPLC to give compound 209 (6.5 mg, 13.7% yield) as whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.94 (s, 1H), 10.46 (s, 1H),8.76 (d, J=1.5 Hz, 1H), 8.05 (m, 1H), 7.84-7.71 (m, 2H), 7.64 (t, J=7.9Hz, 1H), 7.58-7.44 (m, 2H), 6.99 (m, 1H), 5.47 (d, J=17.3 Hz, 1H), 5.18(d, J=17.2 Hz, 2H), 4.67-4.44 (m, 3H), 4.12 (s, 1H), 3.23-3.11 (m, 1H),2.67 (s, 1H), 2.42 (d, J=16.9 Hz, 3H), 2.10 (d, J=9.9 Hz, 1H), 1.78 (d,J=8.4 Hz, 3H), 1.47 (m, 2H), 1.20-1.05 (m, 4H). LC/MS (ESI) m/z: 579[M+H]⁻.

Example 13. Examples of Embodiments of Active Compounds

The Figures provide additional examples of the moieties of the activecompounds described herein, namely, A, B, L, and the central core. Allcombinations of the A, B, L, and central core are consideredspecifically and individually disclosed, and are provided by groupingsonly for efficiency.

Example 14. Non-Limiting Examples of Compounds of Formula I

Table 1 shows illustrative compounds of Formula I with characterizingdata. The compounds of Table 1 are described in PCT Patent ApplicationNo. PCT/US2015/017538 and U.S. patent application Ser. No. 14/631,233titled “Amide Compounds for Treatment of Complement Mediated Disorders”The assay of Example 15 was used to determine the IC₅₀'s of thecompounds. Other standard Factor D inhibition assays are also available.Three ***s are used to denote compounds with an IC₅₀ less than 1micromolar; two **s indicate compound with an IC₅₀ between 1 micromolarand 10 micromolar, and one * denotes compounds with an IC₅₀ greater than10 micromolar.

TABLE 1 Non-limiting Examples of Compounds of Formula I RT min (MethodCmp A or MS No. Structure Name IC₅₀ B) (M + 1) 1

(2S,4R)-1-(2-(3- acetyl-5-(3- cyclopropylureido)- 1H-indol-1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.24 (A) 572 2

(2S,4R)-1-(2-(5-(3- ((2H-tetrazol-5- yl)methyl)ureido)-3-acetyl-1H-indol- 1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.01 (A) 614 3

(1R,3S,5R)-2-(2-(3- acetyl-5-(3- cyclopropylureido)- 1H-indol-1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-2- azabicyclo[3.1.0] hexane-3-carboxamide *** 1.52 (A) 566 4

(2S,4R)-1-(2-(3- acetyl-5-(3-(1- methylcyclopropyl) ureido)-1H-indol-1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.66 (A) 586 5

(1R,3S,5R)-2-(2-(3- acetyl-5-(3- cyclopropylureido)- 1H-indol-1-yl)acetyl)-N-((R)-1- (3-chloro-2- fluorophenyl)ethyl)- 2-azabicyclo[3.1.0] hexane-3- carboxamide *** 1.74 (A) 580 6

(2S,4R)-1-(2-(3- acetyl-5-(3- isopropylureido)- 1H-indol-1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.65 (A) 574 7

(2S,4R)-1-(2-(3- acetyl-5-(3- (isoxazol-3- ylmethyl)ureido)- 1H-indol-1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.49 (A) 613 8

(2S,4R)-1-(2-(3- acetyl-5-(3- (pyrimidin-2- ylmethyl)ureido)-1H-indol-1- yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.35 (A) 624 9

N-(3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluloropyrrolidin-1- yl)-2-oxoethyl)-1H- indol-5- yl)pyrrolidine-1-carboxamide *** 1.61 (A) 586 10

(2S,4R)-1-(2-(3- acetyl-5-(3- cyclopropylureido)- 1H-indol-1-yl)acetyl)-4-fluoro- N-(2-fluoro-3- (trifluoromethoxy)phenyl)pyrrolidine- 2-carboxamide *** 1.80 (A) 608 11

(1R,3S,5R)-2-(2-(3- acetyl-5-(3- cyclopropylureido)- 1H-indol-1-yl)acetyl)-N-(2- fluoro-3- (trifluoromethoxy) phenyl)-2-azabicyclo[3.1.0] hexane-3- carboxamide *** 1.88 (A) 602 12

(1R,3S,5R)-2-(2-(3- acetyl-5- (pyrrolidine-1- carboxamido)-1H-indol-1-yl)acetyl)- N-(3-chloro-2- fluorobenzyl)-2- azabicyclo[3.1.0]hexane-3- carboxamide *** 1.72 (A) 581 13

N-(3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- indol-5-yl)-3,3-difluoropyrrolidine- 1-carboxamide *** 1.77 (A) 622 14

cyclopropyl 3- acetyl-1-(2- ((2S,4R)-2-(3- chloro-2-fluorobenzylcarbamoyl)- 4- fluoropyrrolidin-1- yl)-2-oxoethyl)-1H-indol-5- ylcarbamate *** 1.78 (A) 573 15

cyclopropylmethyl 3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2-fluorobenzylcarbamoyl)- 4- fluoropyrrolidin-1- yl)-2-oxoethyl)-1H-indol-5- ylcarbamate *** 1.96 (A) 587 16

N-(3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- indol-5-yl)-3,3-difluoropiperidine- 1-carboxamide *** 1.82 (A) 636 17

N-(3-acetyl-1-(2- ((2S,4R)-4-fluoro- 2-(2-fluoro-3- (trifluoromethoxy)phenylcarbamoyl) pyrrolidin-1-yl)-2- oxoethyl)-1H- indol-5-yl)-3,3-difluoropiperidine- 1-carboxamide *** 2.06 (A) 672 18

N-(3-acetyl-1-(2- ((2S,4R)-2-(2′- chloro-2- fluorobiphenyl-3-ylcarbamoyl)-4- fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- indol-5-yl)-3,3-difluoropiperidine- 1-carboxamide *** 2.25 (A) 698 19

(2S,4R)-1-(2-(3- acetyl-5-(3- isoxazol-3- ylureido)-1H-indol-1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.60 (A) 599 20

N-(3-acetyl-1-(2- ((2S,4R)-4-fluoro- 2-(6- (trifluoromethyl) pyridin-2-ylcarbamoyl)pyrrolidin- 1-yl)-2- oxoethyl)-1H- indol-5-yl)-3,3-difluoropiperidine- 1-carboxamide *** 1.89 (A) 639 21

(2S,4R)-1-(2-(3- acetyl-5-(3-(2,2,2- trifluoroethyl)ureido)- 1H-indol-1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.72 (A) 614 22

N-(3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- indol-5-yl)-5H- pyrrolo[3,4-d]pyrimidine- 6(7H)-carboxamide *** 1.38 (A) 636 23

(2S,4R)-1-(2-(3- acetyl-5-(3- pyrimidin-5- ylureido)-1H-indol-1-yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.40 (A) 610 24

1-(2-((2S,4R)-2-(2′- chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-5- (3,3- difluoropiperidine-1-carboxamido)- 1H-indazole-3- carboxamide *** 2.09 (A) 700 25

1-(2-((2S,4R)-4- fluoro-2-(2-fluoro- 3- (trifluoromethoxy)phenylcarbamoyl) pyrrolidin-1-yl)-2- oxoethyl)-5-(3- isoxazol-3-ylureido)-1H- indazole-3- carboxamide *** 1.71 (A) 637 26

5-(3,3- difluoropiperidine- 1-carboxamido)-1- (2-((2S,4R)-4-fluoro-2-(2-fluoro- 3- (trifluoromethoxy) phenylcarbamoyl)-2-azabicylco[3.1.0]hexan- 2-yl)-2- oxoethyl)-1H- indazole-3- carboxamide*** 1.90 (A) 674 27

5-(3,3- difluoropiperidine- 1-carboxamido)-1- (2-((1R,3S,5R)-3-(2-fluoro-3- (trifluoromethoxy) phenylcarbamoyl)-2-azabicylco[3.1.0]hexan- 2-yl)-2- oxoethyl)-1H- indazole-3- carboxamide*** 1.97 (A) 668 28

1-(2-((1R,3S,5R)-3- (2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-2-azabicyclo[3.1.0]hexan- 2-yl)-2- oxoethyl)-5-(3,3- difluoropiperidine-1-carboxamido)- 1H-indazole-3- carboxamide *** 2.17 (A) 694 29

1-(2-((2S,4R)-2-(3- (3-chloropyridin-2- yl)-2- fluorophenylcarbamoyl)-4- fluoropyrrolidin-1- yl)-2-oxoethyl)-5- (3,3- difluoropiperidine-1-carboxamido)- 1H-indazole-3- carboxamide *** 1.65 (A) 701 30

1-(2-((2S,4R)-2-(2′- chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-5- (3,3- difluoropyrrolidine-1-carboxamido)- 1H-indazole-3- carboxamide *** 2.03 (A) 686 31

1-(2-((2S,4R)-2-(2′- chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-5- (4,4- difluoropiperidine-1-carboxamido)- 1H-indazole-3- carboxamide *** 2.11 (A) 700 32

1-(2-((2S,4R)-2-(2′- chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-5- (3-(pyrimidin-2-ylmethyl)ureido)- 1H-indazole-3- carboxamide *** 1.69 (A) 688 33

1-(2-((2S,4R)-2-(6- bromopyridin-2- ylcarbamoyl)-4- fluoropyrrolidin-1-yl)-2-oxoethyl)-5- (3,3- difluoropiperidine- 1-carboxamido)-1H-indazole-3- carboxamide *** 1.59 (A) 651 34

1-(2-((1R,3S,5R)-3- (6-bromopyridin-2- ylcarbamoyl)-2-azabicylco[3.1.0]hexan- 2-yl)-2- oxoethyl)-5-(3,3- difluoropiperidine-1-carboxamido)- 1H-indazole-3- carboxamide *** 1.75 (A) 645 35

(2S,4R)-1-(2-(3- acetyl-5-(3,3- difluorocyclopentane- carboxamido)-1H-indol-1-yl)acetyl)- N-(2′-chloro-2- fluorobiphenyl-3- yl)-4-fluoropyrrolidine-2- carboxamide *** 2.61 (A) 683 36

(2S,4R)-1-(2-(3- acetyl-5-(3,3,3- trifluoropropanamido)- 1H-indol-1-yl)acetyl)-N-(2′- chloro-2- fluorobiphenyl-3- yl)-4-fluoropyrrolidine-2- carboxamide *** 2.70 (A) 661 37

tert-butyl 3-acetyl- 1-(2-((2S,4R)-2-(3- chloro-2-fluorobenzylcarbamoyl)- 4- fluoropyrrolidin-1- yl)-2-oxoethyl)-1H-indol-6- ylcarbamate *** 1.90 (A) 589 38

1-(3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- indole-5-carbonyl)- 1,2,3,6-tetrahydropyridin- 4-ylboronic acid *** 0.93 (A) 627 39

(2S,4R)-1-(2-(3- acetyl-5-(2- azabicyclo[2.2.1] heptane-2-carbonyl)-1H-indol-1- yl)acetyl)-N-(3- chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.76 (A) 597 40

(2S,4R)-1-(2-(3- acetyl-5-(3,3- difluoropiperidine- 1-carbonyl)-1H-indol-1-yl)acetyl)- N-(3-chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide *** 1.83 (A) 621 41

3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1- yl)-2-oxoethyl)-N- cyclopropyl-1H- indole-5-carboxamide *** 1.54 (A) 557 42

(2S,4R)-1-(2-(3- acetyl-6-(3- (aminomethyl)- pyrrolidine-1-carbonyl)-1H- indol-1-yl)acetyl)- N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide *** 1.02 (A) 600 43

3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzyl- carbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-N- (methylsulfonyl)- 1H)-indole-6-carboxamide *** 1.60 (A) 595 44

(S)-tert-butyl 3-(3- acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzyl-carbamoyl)-4- fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- indole-6-carboxamido) pyrrolidine-1-carboxylate *** 1.92 (A) 686 45

3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzyl- carbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-N- ((S)-pyrrolidin-3-yl)-1H-indole-6- carboxamide *** 1.10 (A) 586 46

3-acetyl-N-((S)-1- acetylpyrrolidin-3- yl)-1-(2-((2S,4R)-2- (3-chloro-2-fluorobenzylcarbamoyl)- 4- fluoropyrrolidin-1- yl)-2-oxoethyl)-1H-indole-6- carboxamide *** 1.30 (A) 628 48

3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1- yl)-2-oxoethyl)-N- (cyclopropylsulfonyl)-1H-indole-6- carboxamide *** 1.52 (A) 621 49

3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolildin-1- yl)-2-oxoethyl)-N- (pyrrolidin-3- ylmethyl)-1H-indole-6- carboxamide *** 0.70 (A) 600 50

tert-butyl 3-((3- acetyl-1-(2- ((2S,4R)-2-(3- chloro-2-fluorobenzylcarbamoyl)- 4- fluoropyrrolidin-1- yl)-2-oxoethyl)-1H-indole-6- carboxamido)methyl) pyrrolidine-1- carboxylate *** 1.77 (A)700 51

methyl 1-(3-acetyl- 1-(2-((2S,4R)-2-(3- chloro-2-fluorobenzylcarbamoyl)- 4- fluoropyrrolidin-1- yl)-2-oxoethyl)-1H-indole-6- carbonyl)pyrrolidine- 3-carboxylate *** 1.28 (A) 629 52

1-(3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- indole-6- carbonyl)pyrrolidine-3-carboxylic acid *** 1.14 (A) 615 53

3-acetyl-1-(2- ((2S,4R)-2-(3- chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1- yl)-2-oxoethyl)-N- (phenylsulfonyl)- 1H-indole-6-carboxamide *** 1.71 (A) 657 54

1-(2-((2S,4R)-2-(2′- chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-N6- (cyclopropylsulfonyl)-1H-indazole- 3,6-dicarboxamide *** 2.00 (A) 685

Table 2 provides additional compounds within the scope of the presentinvention. The assay of Example 15 was used to determine the IC₅₀'s ofthe compounds. Other standard Factor D inhibition assays are alsoavailable. Three ***s are used to denote compounds with an IC₅₀ lessthan 1 micromolar; two **s indicate compound with an IC₅₀ between 1micromolar and 10 micromolar, and one * denotes compounds with an IC₅₀greater than 10 micromolar.

TABLE 2 Additional Compounds of the Present Invention RT min Cmp (MethodMS No. Structure Name IC₅₀ A or B) (M + 1) 55

1-(2-((2S,4R)-2- (2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-5- pivalamido-1H- pyrazolo[3,4-d]thiazole-3- carboxamide *** 2.20 (A) 644 56

1-(2-((2S,4R)-2- (3-chloro-2- fluorobenzylcarbamoyl)- 4-fluoropyrrolidin-1- yl)-2-oxoethyl)-5- pivalamido-1H- pyrazolo[3,4-d]thiazole-3- carboxamide *** 1.77 (A) 582 57

1-(2-((2S,4R)-2- (2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)- N5-cyclopropyl- 1H-thieno[3,2-c]pyrazole-3,5- dicarboxamide *** 1.96 (A) 627 58

1-(2-((2S,4R)-2- (2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)- N5-methyl-1H- thieno[3,2-c]pyrazole-3,5- dicarboxamide *** 1.82 (A) 601 59

1-(2-((2S,4R)-2- (2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-5- (morpholine-4- carbonyl)-1H-thieno[3,2- c]pyrazole-3- carboxamide *** 1.88 (A) 657 60

1-(2-((2S,4R)-2- (2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)-5- (pyrrolidine-1- carbonyl)-1H-thieno[3,2- c]pyrazole-3- carboxamide *** 2.01 (A) 641 61

1-(2-((2S,4R)-2- (2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)- N5-cyclopentyl- 1H-thieno[3,2-c]pyrazole-3,5- dicarboxamide *** 2.27 (A) 655 62

1-(2-((2S,4R)-2- (2′-chloro-2- fluorobiphenyl-3- ylcarbamoyl)-4-fluoropyrrolidin-1- yl)-2-oxoethyl)- N5,N5-dimethyl- 1H-thieno[3,2-c]pyrazole-3,5- dicarboxamide *** 1.89 (A) 615

Table 3 shows illustrative compounds of Formula I with characterizingdata. The assay of Example 12 was used to determine the IC₅₀'s of thecompounds. Other standard factor D inhibition assays are also available.Three ***s are used to denote compounds with an IC₅₀ less than 1micromolar; two **s indicate compound with an IC₅₀ between 1 micromolarand 10 micromolar, and one * denotes compounds with an IC₅₀ greater than10 micromolar.

TABLE 3 Additional Compounds of the Present Invention RT min (Method A,B, Cmp IC₅₀ C or MS No. Structure Name (Stars) D) (M + 1) 197

N-(3-acetyl- 1-(2- ((2S,4R)-4- fluoro-2- (phenethylcarbamoyl)pyrrolidin-1- yl)-2- oxoethyl)- 1H-indol-5- yl)-3,3-difluoropiperidine-1- carboxamide *** 10.31 (D) 598 198

N-(3-acetyl- 1-(2- ((2S,4R)-4- fluoro-2- ((3- phenylpropyl) carbamoyl)pyrrolidin- 1-yl)-2- oxoethyl)- 1H-indol-5- yl)-3,3-difluoropiperidine-1- carboxamide *** 10.63 (D) 612 199

N-(3-acetyl- 1-(2- ((2S,4R)-4- fluoro-2- ((4- phenylbutyl) carbamoyl)pyrrolidin- 1-yl)-2- oxoethyl)- 1H-indol-5- yl)-3,3-difluoropiperidine-1- carboxamide *** 11.28 (D) 626 196

N-(3-acetyl- 1-(2- ((2S,4R)-2- (benzocarbamoyl)- 4- fluoropyrrolidin-1-yl)-2- oxoethyl)- 1H-indol-5- yl)-3,3- difluoropiperidine-1- carboxamide*** 12.46 (C) 584 205

(S)-N-(3- acetyl-1-(2- (2-((6- methylpyridin- 2-yl)- carbamoyl)-azetidin-1- yl)-2- oxoethyl)- 1H-indol-5- yl)-3,3- difluoropiperidine-1-carboxamide *  9.66 (D) 553 201

N-(3-acetyl- 1-(2- ((2R,4R)-4- fluoro-2-(2- (phenylsulfonamido)ethyl)pyrrolidin- 1-yl)-2- oxoethyl)- 1H-indol-5- yl)-3,3- difluoro-piperidine- 1- carboxamide ** 10.55 (D) 634 185

3-acetyl-N- (cyclopropylsulfonyl)- 1- (2-((2S,4R)- 4-fluoro-2-(phenethylcarbamoyl) pyrrolidin-1- yl)-2- oxoethyl)- 1H-indole- 5-carboxamide *  7.73 (D) 583 190

3-acetyl-N- (cyclopropylsulfonyl)- 1- (2-((2S,4R)- 4-fluoro-2- ((3-phenylpropyl) carbamoyl) pyrrolidin- 1-yl)-2- oxoethyl)- 1H-indole- 5-carboxamide **  8.07 (D) 595 (M − 1) 180

3-acetyl-1- (2-((2S,4R)- 2- (benzylcarbamoyl)- 4- fluoropyrrolidin-1-yl)-2- oxoethyl)- N- (cyclopropylsulfonyl)- 1H-indole- 5- carboxamide** 11.11 (C) 569 195

3-acetyl-N- (cyclopropylsulfonyl)- 1- (2-((2S,4R)- 4-fluoro-2- ((4-phenylbutyl) carbamoyl) pyrrolidin- 1-yl)-2- oxoethyl)- 1H-indole- 5-carboxamide * 12.66 (C) 609 (M − 1) 174

3-acetyl-N- (cyclopropylsulfonyl)- 1- (2-((2R,4R)- 4-fluoro-2- (2-(phenylsulfonylamido) ethyl)pyrrolidin- 1-yl)-2- oxoethyl)- 1H-indole-5- carboxamide *  8.06 (D) 617 (M − 1) 206

5-(3,3- difluoropiperidine- 1- carbonyl)-1- (2- ((1R,3S,4S)- 3-((6-methyl- pyridin-2- yl)- carbamoyl)- 2-aza- bicyclo[2.2.1] heptan-2-yl)-2- oxoethyl)- 1H-indole- 3- carboxamide **  2.07 (B) 594 207

N-(3-acetyl- 1-(2- ((2S,4R)-2- ((6-bromo- pyridin-2- yl)carbamoyl)-4-fluoro- pyrrolidin- 1-yl)-2- oxoethyl)- 1H-indazol- 5-yl)-3,3-difluoro- pyrrolidine- 1- carboxamide *** 12.88 (C) 637 208

3-acetyl-1- (2-((2S,4R)- 2-((3- chloro-2- fluorobenzyl) carbamoyl)- 4-fluoropyrrolidin- 1-yl)-2- oxoethyl)- N- (cyclopropylsulfonyl)-1H-indole- 5- carboxamide *** 12.87 (C) 622 209

N5- (cyclopropylsulfonyl)- 1- (2-((1R,4S)- 3-((6- methyl- pyridin-2-yl)carbamoyl)- 2-aza- bicyclo[2.2.1] heptan-2- yl)-2- oxoethyl)-1H-indole- 3,5- dicarboxamide *  1.30 (B) 579 230

2S,4R)-1- (2-(3-acetyl- 5-(2,2- difluorocyclopentane- 1-carboxamido)-1H- indazol-1- yl)acetyl)- N-(6- bromopyridin- 2-yl)-4-fluoropyrrolidine- 2- carboxamide *** 11.88 (D) 633 (M − 2) 231

3-acetyl-N- (cyclopropylsulfonyl)- 1- (2-((2S,4R)- 4-fluoro-2- ((3-phenylpropyl) carbamoyl) pyrrolidin- 1-yl)-2- oxoethyl)- 1H-indole- 5-carboxamide *** 11.97 (D) 647 (M − 2) 232

3-acetyl-1- (2-((2S,4R)- 2-((6- bromopyridin- 2- yl)carbamoyl)- 4-fluoropyrrolidin- 1-yl)-2- oxoethyl)- N- (cyclopropylsulfonyl)- 1H-indazole-6- carboxamide **  8.07 (D) 595 (M − 1) 233

3-acetyl-1- (2-((2S,4R)- 2-((6- bromopyridin- 2-yl)- carbamoyl)-4-fluoro- pyrrolidin- 1-yl)-2- oxoethyl)- N- (cyclopropylsulfonyl)-1H-indazole-6- carboxamide ***  8.36 (D) 635 (M − 1) 234

3-acetyl-1- (2- ((1R,3S,5R)- 3-((6- bromopyridin- 2- yl)carbamoyl)-5-methyl- 2- azabicyclo [3.1.0]hexan- 2-yl)-2- oxoethyl)- N-(cyclopropylsulfonyl)- 1H- indazole-6- carboxamide **  9.57 (C) 644

Example 15. Human Factor D Assay

Human Factor D (purified from human serum, Complement Technology, Inc.)at 80 nM final concentration is incubated with test compound at variousconcentrations for 5 minutes at room temperature in 50 mM Tris, 1M NaCl,pH 7.5. A synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman's reagent)are added to final concentrations of 100 μM each. Absorbance at 405 nm(A₄₀₅) is recorded at 30 second intervals for 30 minutes using amicroplate spectrophotometer. IC₅₀ values are calculated by nonlinearregression of complement Factor D reaction rates as a function of testcompound concentration.

Example 16. Hemolysis Assay

The hemolysis assay was previously described by G. Ruiz-Gomez, et al.,J. Med. Chem. (2009) 52: 6042-6052. Prior to the assay, the optimumconcentration of Normal Human Serum (NHS) needed to achieve 100% lysisof rabbit erythrocytes (RE) is determined by titration. In the assay,NHS (Complement Technology) is diluted in GVB⁰ Buffer (0.1% gelatin, 5mM Veronal, 145 mM NaCl, 0.025% NaN₃, pH 7.3, Complement Technology)plus 10 mM Mg-EGTA and incubated with test compound at variousconcentrations for 15 minutes at 37° C. RE (Complement Technology)freshly suspended in GVB⁰ plus 10 mM Mg-EGTA are added to a finalconcentration of 1×10⁸ cells/mL and reactions are incubated for 30minutes at 37° C. Positive control reactions (100% lysis) consist ofGVB⁰ plus 10 mM Mg-EGTA with NHS and RE but without test compound;negative control reactions (0% lysis) consist of GVB⁰ plus 10 mM Mg-EGTAwith RE only. Samples are centrifuged at 2000 g for 3 minutes andsupernatants collected. Absorbance at 405 nm (A₄₀₅) is recorded using amicroplate spectrophotometer. IC₅₀ values are calculated by nonlinearregression from the percentage of hemolysis as a function of testcompound concentration.

Example 17. Effect of Combination Therapy

The combinatorial efficacy of two compounds on the complementalternative pathway (CAP) is assessed by determining the effect of twocompounds mixed together at various concentrations with Normal HumanSerum (NHS) on the hemolysis of rabbit erythrocytes (RE) or theproduction of terminal complement complex (TCC). In both assays the twotest compounds are prepared individually in seven-point dilution series,with an eighth sample for each containing solvent alone, and each of the64 possible combinations is tested in duplicate or triplicate wells.

In the hemolysis assay, NHS (Complement Technology) diluted to 10% inGVB⁰ Buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN₃, pH7.3, Complement Technology) plus 10 mM Mg-EGTA is incubated with thecompounds at various concentrations for 15 minutes at 37° C. RE(Complement Technology) freshly suspended in GVB⁰ plus 10 mM Mg-EGTA areadded to a final concentration of 1×10⁸ cells/mL and reactions areincubated for 30 minutes at 37° C. Positive control reactions consist ofGVB⁰ plus Mg-EGTA with NHS and RE but without test compounds; negativecontrol reactions consist of GVB⁰ plus Mg-EGTA with RE only. Samples arecentrifuged at 2000 g for 3 minutes and supernatants collected.Absorbance at 405 nM (A₄₀₅) is recorded using a microplatespectrophotometer.

The assay for TCC production is conducted using the Complement systemAlternative Pathway Wieslab assay kit (Euro Diagnostica). NHS diluted to5.56% in the provided diluent is incubated with each compound in thewells of the provided assay plates for 60 minutes at 37° C. The wellsare emptied and washed with the provided wash solution, incubated with100 enzyme-linked detection antibody at 37° C. for 30 minutes, emptiedand washed again, and incubated with 100 μL substrate at roomtemperature for 30 minutes. The provided quantitation standards are usedas described by the manufacturer. Positive control reactions consist ofdiluent with NHS but without test compounds; negative control reactionsconsist of diluent only. After the 30 minute incubation, the A₄₀₅ ofeach well is recorded using a microplate spectrophotometer. TCCproduction is quantitated from A₄₀₅ by reference to the quantitationstandards.

Combinatorial effects in both assays are analyzed using thethree-dimensional surface-graphing method of Prichard, M. N. and C.Shipman, Jr., Antiviral Research 1990, 14: 181-205, wherein the X-axisand Y-axis indicate test compound concentrations and the Z-axisindicates the difference between measured inhibition and a theoreticallydetermined additive inhibition. For an additive combinatorialrelationship the surface graph will resemble a horizontal plane of zeroheight, whereas positive surface peaks indicate greater inhibition thanexpected and therefore synergy, and negative surface peaks indicate lessinhibition than expected and therefore antagonism.

Combinatorial efficacy on the hemolysis of rabbit erythrocytes (RE) canbe examined using a compound described herein and a wide variety ofsecond active agents. For example, one non-limiting example is thepeptidic complement C3 inhibitor compstatin (Tocris Bioscience). Inanother example, the combinatorial efficacy of a compound as describedherein and a complement Factor B inhibitor can be assessed, for example,using the structure below (See compound 84 in WO2013/192345).Alternatively, the combinatorial efficacy of a compound of the presentinvention and a monoclonal antibody directed against complement C5protein (anti-C5, Quidel A217, murine monoclonal antibody to humancomplement C5, isotype IgG1K) on the production of terminal complementcomplex (TCC) can be assessed. In another non-limiting example, thecombinatorial efficacy of an active compound of the invention and thebroad spectrum inhibitor FUT-175 (BD Biosciences) on the hemolysis ofrabbit erythrocytes (RE) is assessed.

Synergy and antagonism volumes are the summed volumes of peaksrespectively above and below the Z=0 plane on the surface graph. Volumesare determined using 95% confidence limits to assure significance.Compounds are considered additive for volumes between −25 and 25.Compounds are considered slightly synergistic for volumes between 25 and50, moderately synergistic for volumes between 50 and 100, and stronglysynergistic for volumes greater than 100. Compounds are consideredslightly antagonistic for volumes between −25 and −50, moderatelyantagonistic for volumes between −50 and −100, and strongly antagonisticfor volumes less than −100. Results are presented as means±standarddeviations from two or three independent experiments.

This specification has been described with reference to embodiments ofthe invention. However, one of ordinary skill in the art appreciatesthat various modifications and changes can be made without departingfrom the scope of the invention as set forth in the claims below.Accordingly, the specification is to be regarded in an illustrativerather than a restrictive sense, and all such modifications are intendedto be included within the scope of invention.

We claim:
 1. A method for the treatment of a disorder mediated bycomplement factor D, comprising administering an effective amount to ahost in need thereof a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: Q¹ isC(R¹R^(1′)); Q² is C(R²R^(2′)); Q³ is C(R³R^(3′)); X¹ is N and X² is CH;R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently selected fromhydrogen, halogen, hydroxyl, nitro, cyano, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkynyl, C₂-C₆alkanoyl,C₁-C₆thioalkyl, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)OR⁹, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰,—NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; R⁹ and R¹⁰ areindependently selected from hydrogen, C₁-C₆alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), and—O—C₀-C₄alkyl(C₃-C₇cycloalkyl); or R¹ and R² are linked to form a 3- to6-membered carbocyclic or aryl ring; or R² and R³ are linked to form a3- to 6-membered carbocyclic ring; or R¹ and R^(1′), or R² and R^(2′),or R³ and R^(3′) are linked to form a 3- to 6-membered carbocyclic spiroring; or R¹ and R^(1′), or R² and R^(2′), or R³ and R^(3′) are linked toform a 3- to 6-membered heterocyclic spiro ring; each of which ring isunsubstituted or substituted with one or more substituents independentlyselected from halogen, hydroxyl, cyano, —COOH, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; orR¹ and R^(1′) or R² and R^(2′) are taken together to form a carbonylgroup; A is a group selected from:

R⁵ and R⁶ are independently selected from —CHO, —C(O)NH₂, —C(O)NH(CH₃),C₂-C₆alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH,—SO₂NH₂, vinyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkoxy,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl),—P(O)(OR⁹)₂, —OC(O)R⁹, —C(O)OR⁹, —C(O)N(CH₂CH₂R⁹)(R¹⁰), —NR⁹C(O)R¹⁰,phenyl, and 5- to 6-membered heteroaryl; R⁸ and R^(8′) are independentlyselected from hydrogen, halogen, hydroxyl, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) can be taken together with the carbonthat they are bonded to form a 3-membered carbocyclic ring; X¹¹ is N orCR¹¹; X¹² is CR¹²; X¹³ is CR¹³; X¹⁴ is N or CR¹⁴; one of R¹² and R¹³ isselected from R³¹ and the other of R¹² and R¹³ is selected from R³²; R³¹is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and —C(NR⁹)NR⁹R¹⁰, each ofwhich R³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy is unsubstituted or substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, amino, —COOH, —CONH₂C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,and each of which R³¹ is also optionally substituted with onesubstituent selected from phenyl and 4- to 7-membered heterocyclecontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS; which phenyl or 4- to 7-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl)(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, andC₁-C₂haloalkoxy; R³² is selected from —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰,—NR⁹C(O)OR²³, —NR⁹C(O)R²¹, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, and—NR⁹C(O)NR²⁴R²⁵; R¹¹ and R¹⁴ are independently selected from hydrogen,halogen, hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₂-C₆alkenyl(aryl),C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), C₂-C₆alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; R²¹and R²² are independently selected from hydrogen, hydroxyl, cyano,amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; R²³ is independently selected fromC₁-C₆alkyl, C₁-C₆haloalkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(aryl)C₀-C₄alkyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkyl having1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5-or 6-membered unsaturated or aromatic heterocycle)C₀-C₄alkyl having 1,2, or 3 heteroatoms independently selected from N, O, and S; R²⁴ and R²⁵are taken together with the nitrogen to which they are attached to forma 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to10-membered bicyclic heterocyclic group having fused, spiro, or bridgedrings and each R²⁴ and R²⁵; L is

R¹⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹⁸ andR^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; m is 0, 1, 2, or 3; B is a monocyclic orbicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; amonocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or4 heteroatoms independently selected from N, O, and S and from 4 to 7ring atoms per ring; C₂-C₆alkenyl; C₂-C₆alkynyl; —(C₀-C₄alkyl)(aryl);—(C₀-C₄alkyl)(heteroaryl); or —(C₀-C₄alkyl)(biphenyl), and B isunsubstituted or substituted with one or more substituents independentlyselected from R³³ and R³⁴, and 0 or 1 substituents selected from R³⁵ andR³⁶; R³³ is selected from halogen, hydroxyl, —COOH, cyano, C₁-C₆alkyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy; R³⁴ is selected from nitro, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³,-JOSO₂OR²¹, —C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²²,-JOP(O)(OR²¹)(OR²²), -JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹⁾R²²,-JP(O)(OR²¹)R²², -JOP(O)R²¹R²², -JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²),-JSP(O)(OR²¹)(R²²), -JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²²,-JNR⁹S(O)NR¹⁰R²², -JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²²,-JNR²¹SO₂R²², -JC(O)NR²¹SO₂R²², -JC(NH₂)NR²², -JC(NH₂)NR⁹S(O)₂R²²,-JOC(O)NR²¹R²², -JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²²,-JC(O)NR²⁴R²⁵, -JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹R²², —CCR²¹,—(CH₂)₁₋₄OC(O)R²¹, and -JC(O)OR²³; each of which R³⁴ may beunsubstituted or substituted with one or more substituents independentlyselected from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂,—Si(CH₃)₃, —COOH, —CONH₂, —P(O)(OH)₂, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₆alkylester, C₁-C₄alkylamino,C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; R³⁵ is selectedfrom naphthyl, naphthyloxy, indanyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl containing 1 or 2 heteroatoms selected fromN, O, and S, and bicyclic heterocycle containing 1, 2, or 3 heteroatomsindependently selected from N, O, and S, and containing 4- to 7-ringatoms in each ring; each of which R³⁵ is unsubstituted or substitutedwith one or more substituents independently selected from halogen,hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy; R³⁶ is selected from tetrazolyl, (phenyl)C₀-C₂alkyl,(phenyl)C₁-C₂alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently selected from N, O, B, and S, eachof which R³⁶ is unsubstituted or substituted with one or moresubstituents independently selected from halogen, hydroxyl, nitro,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, —OSi(CH₃)₂C(CH₃)₃,—Si(CH₃)₂C(CH₃)₃, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; and J is selectedfrom a covalent bond, C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene,and C₂-C₄alkynylene.
 2. The method of claim 1, wherein the host is ahuman.
 3. The method of claim 2, wherein the disorder is age-relatedmacular degeneration (AMD) or retinal degeneration.
 4. The method ofclaim 2, wherein the disorder is multiple sclerosis, arthritis, or COPD.5. The method of claim 2, wherein the disorder is an ophthalmic disease.6. The method of claim 2, wherein the disorder is paroxysmal nocturnalhemoglobinuria (PNH).
 7. The method of claim 2, wherein the disorder isa respiratory disease.
 8. The method of claim 2, wherein the disorder iscardiovascular disease.
 9. The method of claim 2, wherein the disorderis atypical or typical hemolytic uremic syndrome.
 10. The method ofclaim 2, wherein the disorder is rheumatoid arthritis.
 11. The method ofclaim 2, wherein the disorder is C3 glomerulonephritis.
 12. The methodof claim 2, wherein the disorder is MPGN II.
 13. The method of claim 2,wherein the disorder is membrane proliferative glomerulonephritis. 14.The method of claim 2, wherein the disorder is atypical hemolytic uremicsyndrome.
 15. The method of claim 2, wherein the

ring is selected from:


16. The method of claim 2, wherein: a) R¹ and R^(1′), or R² and R^(2′),or R³ and R^(3′) are linked to form a 3- to 6-membered carbocyclic spiroring; or b) R¹ and R^(1′), R² and R^(2′) or R³ and R^(3′) are linked toform a 3- to 6-membered heterocyclic spiro ring; or c) R¹ and R² arelinked to form a 3- to 6-membered carbocyclic or aryl ring; or d) R² andR³ are linked to form a 3- to 6-membered carbocyclic ring.
 17. Themethod of claim 2, wherein B is selected from —(C₀-C₄alkyl)(aryl);—(C₀-C₄alkyl)(heteroaryl); and —(C₀-C₄alkyl)(biphenyl) wherein B isunsubstituted or substituted with one or more substituents independentlychosen from R³³ and R³⁴, and 0 or 1 substituents chosen from R³⁵ andR³⁶.
 18. The method of claim 3, wherein the —(C₀-C₄alkyl)(aryl) group isphenyl or benzyl optionally substituted with halogen, hydroxyl, —COOH,cyano, C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰,—SO₂R⁹, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, or -JC₃-C₇cycloalkyl.
 19. The method of claim 17,wherein the —(C₀-C₄alkyl)(heteroaryl) group is imidazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl,thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl orpyrrolyl optionally substituted with halogen, hydroxyl, —COOH, cyano,C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, or -JC₃-C₇cycloalkyl.
 20. The method of claim 17,wherein the —(C₀-C₄alkyl)(biphenyl) group is biphenyl optionallysubstituted with halogen, hydroxyl, —COOH, cyano, C₁-C₆alkyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆thioalkyl, or-JC₃-C₇cycloalkyl.
 21. The method of claim 2, wherein B is selectedfrom:


22. The method of claim 2, wherein B is selected from:


23. The method of claim 2, wherein R³² is selected from:


24. The method of claim 2, wherein the compound is selected from:


25. The method of claim 2, wherein the disorder is fatty liver disease.26. The method of claim 2, wherein the disorder is liver inflammation,cirrhosis, or liver failure.
 27. The method of claim 2, wherein thedisorder is Dermatomyositis.
 28. The method of claim 2, wherein thedisorder is amyotrophic lateral sclerosis.
 29. The method of claim 2,wherein the disorder is nonalcoholic steatohepatitis.
 30. The method ofclaim 5, wherein the compound is administered to the intravitreal,subchoroidal, or suprachoroidal space of the eye.
 31. The method ofclaim 2, wherein the compound is administered in combination with aneffective amount of an additional active agent.